Tamper resistant dosage forms

ABSTRACT

The present invention relates to pharmaceutical dosage forms, for example to a tamper resistant dosage form including an opioid analgesic, and processes of manufacture, uses, and methods of treatment thereof.

This application claims priority from U.S. Provisional Application Ser.No. 60/840,244, filed Aug. 25, 2006, the disclosure of which is herebyincorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to pharmaceutical dosage forms, forexample to a tamper resistant dosage form including an opioid analgesic,and processes of manufacture, uses, and methods of treatment thereof.

BACKGROUND OF THE INVENTION

Pharmaceutical products are sometimes the subject of abuse. For example,a particular dose of opioid agonist may be more potent when administeredparenterally as compared to the same dose administered orally. Someformulations can be tampered with to provide the opioid agonistcontained therein for illicit use. Controlled release opioid agonistformulations are sometimes crushed, or subject to extraction withsolvents (e.g., ethanol) by drug abusers to provide the opioid containedtherein for immediate release upon oral or parenteral administration.

Controlled release opioid agonist dosage forms which can liberate aportion of the opioid upon exposure to ethanol, can also result in apatient receiving the dose more rapidly than intended if a patientdisregards instructions for use and concomitantly uses alcohol with thedosage form.

There continues to exist a need in the art for pharmaceutical oraldosage forms comprising an opioid agonist without significantly changedopioid release properties when in contact with alcohol and/or withresistance to crushing.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the present invention toprovide an oral extended release dosage form comprising an active agentsuch as an opioid analgesic which is tamper resistant.

It is an object of certain embodiments of the present invention toprovide an oral extended release dosage form comprising an active agentsuch as an opioid analgesic which is resistant to crushing.

It is an object of certain embodiments of the present invention toprovide an oral extended release dosage form comprising an active agentsuch as an opioid analgesic which is resistant to alcohol extraction anddose dumping when concomitantly used with or in contact with alcohol.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation in the form of a tablet or multiparticulates, wherein the tablet or the individual multi particulatescan be at least flattened without breaking, characterized by a thicknessof the tablet or of the individual multi particulate after theflattening which corresponds to no more than about 60% of the thicknessof the tablet or the individual multi particulate before flattening, andwherein said flattened tablet or the flattened multi particulatesprovide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C., characterized by the percent amount of active releasedat 0.5 hours of dissolution that deviates no more than about 20% pointsfrom the corresponding in-vitro dissolution rate of a non-flattenedreference tablet or reference multi particulates.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation in the form of a tablet or multiparticulates, wherein the tablet or the individual multi particulatescan at least be flattened without breaking, characterized by a thicknessof the tablet or the individual multi particulate after the flatteningwhich corresponds to no more than about 60% of the thickness of thetablet or the individual multi particulate before flattening, andwherein the flattened or non flattened tablet or the flattened or nonflattened multi particulates provide an in-vitro dissolution rate, whenmeasured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C.,characterized by the percent amount of active released at 0.5 hours ofdissolution that deviates no more than about 20% points from thecorresponding in-vitro dissolution rate measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. without ethanol, using a flattened and non flattenedreference tablet or flattened and non flattened reference multiparticulates, respectively.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000.000; and    -   (2) at least one active agent; and

wherein the composition comprises at least about 80% (by wt)polyethylene oxide.

According to certain such embodiments the active agent is oxycodonehydrochloride and the composition comprises more than about 5% (by wt)of the oxycodone hydrochloride.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one active agent;    -   (2) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (3) at least one polyethylene oxide having, based on rheological        measurements, a molecular weight of less than 1,000,000.

In certain embodiments, the present invention is directed to a processof preparing a solid oral extended release pharmaceutical dosage form,comprising at least the steps of:

-   -   (a) combining at least        -   (1) at least one polyethylene oxide having, based on            rheological measurements, an approximate molecular weight of            at least 1,000,000, and        -   (2) at least one active agent,        -   to form a composition;    -   (b) shaping the composition to form an extended release matrix        formulation; and    -   (c) curing said extended release matrix formulation comprising        at least a curing step of subjecting the extended release matrix        formulation to a temperature which is at least the softening        temperature of said polyethylene oxide for a time period of at        least about 1 minute.

In certain embodiments, the present invention is directed to a processof preparing a solid oral extended release pharmaceutical dosage form,comprising at least the steps of:

-   -   (a) combining at least        -   (1) at least one polyethylene oxide having, based on            rheological measurements, an approximate molecular weight of            at least 1,000,000, and        -   (2) at least one active agent,        -   to form a composition;    -   (b) shaping the composition to form an extended release matrix        formulation; and    -   (c) curing said extended release matrix formulation comprising        at least a curing step wherein said polyethylene oxide at least        partially melts.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation comprising an active agent in the form of atablet or multi particulates,

wherein the tablet or the individual multi particulates can at least beflattened without breaking, characterized by a thickness of the tabletor of the individual multi particulate after the flattening whichcorresponds to no more than about 60% of the thickness of the tablet orthe individual multi particulate before flattening, and wherein saidflattened tablet or the flattened multi particulates provide an in-vitrodissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpmin 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.,characterized by the percent amount of active agent released at 0.5hours of dissolution that deviates no more than about 20% points fromthe corresponding in-vitro dissolution rate of a non-flattened referencetablet or reference multi particulates.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation comprising an active agent in the form of atablet or multi particulates,

wherein the tablet or the individual multi particulates can at least beflattened without breaking, characterized by a thickness of the tabletor of the individual multi particulate after the flattening whichcorresponds to no more than about 60% of the thickness of the tablet orthe individual multi particulate before flattening, and wherein saidflattened tablet or the flattened multi particulates and thenon-flattened reference tablet or reference multi particulates providean in-vitro dissolution rate, which when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C., is between about 5 and about 40% (by wt) active agentreleased after 0.5 hours.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation comprising an active agent in the form of atablet or multi particulates,

wherein the tablet or the individual multi particulates can at least beflattened without breaking, characterized by a thickness of the tabletor the individual multi particulate after the flattening whichcorresponds to no more than about 60% of the thickness of the tablet orthe individual multi particulate before flattening, and wherein theflattened or non flattened tablet or the flattened or non flattenedmulti particulates provide an in-vitro dissolution rate, when measuredin a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastricfluid without enzymes (SGF) comprising 40% ethanol at 37° C.,characterized by the percent amount of active agent released at 0.5hours of dissolution that deviates no more than about 20% points fromthe corresponding in-vitro dissolution rate measured in a USP Apparatus1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. without ethanol, using a flattened and non flattenedreference tablet or flattened and non flattened reference multiparticulates, respectively.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation comprising an active agent in the form of atablet or multi particulates,

wherein the tablet or the individual multi particulates can at least beflattened without breaking, characterized by a thickness of the tabletor the individual multi particulate after the flattening whichcorresponds to no more than about 60% of the thickness of the tablet orthe individual multi particulate before flattening, and wherein theflattened or non flattened tablet or the flattened or non flattenedmulti particulates provide an in-vitro dissolution rate, which whenmeasured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) comprising 40% or 0% ethanol at 37°C., is between about 5 and about 40% (by wt) active agent released after0.5 hours.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) at least one active agent selected from opioid analgesics;        and

wherein the composition comprises at least about 80% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 10 mg oxycodone hydrochloride; and

wherein the composition comprises at least about 85% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 15 mg or 20 mg oxycodone hydrochloride; and

wherein the composition comprises at least about 80% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 40 mg oxycodone hydrochloride; and

wherein the composition comprises at least about 65% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 60 mg or 80 mg oxycodone hydrochloride; and

wherein the composition comprises at least about 60% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 8 mg hydromorphone hydrochloride; and

wherein the composition comprises at least about 94% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 12 mg hydromorphone hydrochloride; and

wherein the composition comprises at least about 92% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 32 mg hydromorphone hydrochloride; and

wherein the composition comprises at least about 90% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising a composition comprising at least:

-   -   (1) at least one active agent selected from opioid analgesics;    -   (2) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (3) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of less than        1,000,000.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, a molecular weight of at least 800,000; and    -   (2) at least one active agent selected from opioid analgesics;        and

wherein the composition comprises at least about 80% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) at least one active agent; and

wherein the extended release matrix formulation when subjected to anindentation test has a cracking force of at least about 110 N.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000.000; and    -   (2) at least one active agent; and

wherein the extended release matrix formulation when subjected to anindentation test has a “penetration depth to crack distance” of at leastabout 1.0 mm.

In certain embodiments, the present invention is directed to a method oftreatment wherein a dosage form according to the invention comprising anopioid analgesic is administered for treatment of pain to a patient inneed thereof.

In certain embodiments, the present invention is directed to the use ofa dosage form according to the invention comprising an opioid analgesicfor the manufacture of a medicament for the treatment of pain.

In certain embodiments, the present invention is directed to the use ofhigh molecular weight polyethylene oxide that has, based on rheologicalmeasurements, an approximate molecular weight of at least 1,000,000, asmatrix forming material in the manufacture of a solid extended releaseoral dosage form comprising an active selected from opioids forimparting to the solid extended release oral dosage form resistance toalcohol extraction.

In certain embodiments, the present invention is directed to a processof preparing a solid oral extended release pharmaceutical dosage form,comprising at least the steps of:

-   -   (a) combining at least        -   (1) at least one polyethylene oxide having, based on            rheological measurements, a molecular weight of at least            1,000,000, and        -   (2) at least one active agent,        -   to form a composition;    -   (b) shaping the composition to form an extended release matrix        formulation; and    -   (c) curing said extended release matrix formulation comprising        at least a curing step of subjecting the extended release matrix        formulation to a temperature which is at least the softening        temperature of said polyethylene oxide for a time period of at        least 5 minutes.

According to certain embodiments of the invention the solid extendedrelease pharmaceutical dosage form is for use as a suppository.

The term “extended release” is defined for purposes of the presentinvention as to refer to products which are formulated to make the drug

available over an extended period after ingestion thereby allowing areduction in dosing frequency compared to a drug presented as aconventional dosage form (e.g. as a solution or an immediate releasedosage form).

The term “immediate release” is defined for the purposes of the presentinvention as to refer to products which are formulated to allow the drugto dissolve in the gastrointestinal contents with no intention ofdelaying or prolonging the dissolution or absorption of the drug.

The term “solid oral extended release pharmaceutical dosage form” refersto the administration form comprising a unit dose of active agent inextended release form such as an “extended release matrix formulation”and optionally other adjuvants and additives conventional in the art,such as a protective coating or a capsule and the like, and optionallyany other additional features or components that are used in the dosageform. Unless specifically indicated the term “solid oral extendedrelease pharmaceutical dosage form” refers to said dosage form in intactform i.e. prior to any tampering. The extended release pharmaceuticaldosage form can e.g. be a tablet comprising the extended release matrixformulation or a capsule comprising the extended release matrixformulation in the form of multi particulates. The “extended releasepharmaceutical dosage form” may comprise a portion of active agent inextended release form and another portion of active agent in immediaterelease form, e.g. as an immediate release layer of active agentsurrounding the dosage form or an immediate release component includedwithin the dosage form.

The term “extended release matrix formulation” is defined for purposesof the present invention as shaped solid form of a compositioncomprising at least one active agent and at least one extended releasefeature such as an extended release matrix material such as e.g. highmolecular weight polyethylene oxide. The composition can optionallycomprise more than these two compounds namely further active agents andadditional retardants and/or other materials, including but not limitedto low molecular weight polyethylene oxides and other adjuvants andadditives conventional in the art.

The term “bioequivalent/bioequivalence” is defined for the purposes ofthe present invention to refer to a dosage form that provides geometricmean values of C_(max), AUC_(t), and AUC_(inf) for an active agent,wherein the 90% confidence intervals estimated for the ratio(test/reference) fall within the range of 80.00% to 125.00%. Preferably,the mean values C_(max), AUC_(t), and AUC_(inf) fall within the range of80.00% to 125.00% as determined in both the fed and the fasting states.

The term “polyethylene oxide” is defined for purposes of the presentinvention as having a molecular weight of at least 25,000, measured asis conventional in the art, and preferably having a molecular weight ofat least 100,000. Compositions with lower molecular weight are usuallyreferred to as polyethylene glycols.

The term “high molecular weight polyethylene oxide” is defined forproposes of the present invention as having an approximate molecularweight of at least 1,000,000. For the purpose of this invention theapproximate molecular weight is based on rheological measurements.Polyethylene oxide is considered to have an approximate molecular weightof 1,000,000 when a 2% (by wt) aqueous solution of said polyethyleneoxide using a Brookfield viscometer Model RVF, spindle No. 1, at 10 rpm,at 25° C. shows a viscosity range of 400 to 800 mPa s (cP). Polyethyleneoxide is considered to have an approximate molecular weight of 2,000,000when a 2% (by wt) aqueous solution of said polyethylene oxide using aBrookfield viscometer Model RVF, spindle No. 3, at 10 rpm, at 25° C.shows a viscosity range of 2000 to 4000 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight of 4,000,000 whena 1% (by wt) aqueous solution of said polyethylene oxide using aBrookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 1650 to 5500 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight of 5,000,000 whena 1% (by wt) aqueous solution of said polyethylene oxide using aBrookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 5500 to 7500 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight of 7,000,000 whena 1% (by wt) aqueous solution of said polyethylene oxide using aBrookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 7500 to 10,000 mPa s (cP). Polyethylene oxideis considered to have an approximate molecular weight of 8,000,000 whena 1% (by wt) aqueous solution of said polyethylene oxide using aBrookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C.shows a viscosity range of 10,000 to 15,000 mPa s (cP). Regarding thelower molecular weight polyethylene oxides; Polyethylene oxide isconsidered to have an approximate molecular weight of 100,000 when a 5%(by wt) aqueous solution of said polyethylene oxide using a Brookfieldviscometer Model RVT, spindle No. 1, at 50 rpm, at 25° C. shows aviscosity range of 30 to 50 mPa s (cP) and polyethylene oxide isconsidered to have an approximate molecular weight of 900,000 when a 5%(by wt) aqueous solution of said polyethylene oxide using a Brookfieldviscometer Model RVF, spindle No. 2, at 2 rpm, at 25° C. shows aviscosity range of 8800 to 17,600 mPa s (cP).

The term “low molecular weight polyethylene oxide” is defined forpurposes of the present invention as having, based on the rheologicalmeasurements outlined above, an approximate molecular weight of lessthan 1,000,000.

The term “direct compression” is defined for purposes of the presentinvention as referring to a tableting process wherein the tablet or anyother compressed dosage form is made by a process comprising the stepsof dry blending the compounds and compressing the dry blend to form thedosage form, e.g. by using a diffusion blend and/or convection mixingprocess (e.g. Guidance for Industry, SUPAC-IR/MR: Immediate Release andModified Release Solid Oral Dosage Forms, Manufacturing EquipmentAddendum).

The term “bed of free flowing tablets” is defined for the purposes ofthe present invention as referring to a batch of tablets that are keptin motion with respect to each other as e.g. in a coating pan set at asuitable rotation speed or in a fluidized bed of tablets. The bed offree flowing tablets preferably reduces or prevents the sticking oftablets to one another.

The term “flattening” and related terms as used in the context offlattening tablets or other dosage forms in accordance with the presentinvention means that a tablet is subjected to force applied from adirection substantially perpendicular to the diameter and substantiallyinline with the thickness of e.g. a tablet. The force may be appliedwith a carver style bench press (unless expressly mentioned otherwise)to the extent necessary to achieve the target flatness/reducedthickness. According to certain embodiments of the invention theflattening does not result in breaking the tablet in pieces, however,edge spits and cracks may occur. The flatness is described in terms ofthe thickness of the flattened tablet compared to the thickness of thenon-flattened tablet expressed in % thickness, based on the thickness ofthe non flattened tablet. Apart from tablets, the flattening can beapplied to any shape of a dosage form, wherein the force is applied froma direction substantially in line with the smallest diameter (i.e. thethickness) of the shape when the shape is other than spherical and fromany direction when the shape is spherical. The flatness is thendescribed in terms of the thickness/smallest diameter of the flattenedshape compared to the thickness/smallest diameter of the non-flattenedshape expressed in % thickness, based on the thickness/smallest diameterof the non flattened shape, when the initial shape is non spherical, orthe % thickness, based on the non flattened diameter when the initialshape is spherical. The thickness is measured using a thickness gauge(e.g., digital thickness gauge or digital caliper) In FIGS. 4 to 6tablets are shown that where flattened using a carver bench press. Theinitial shape of the tablets is shown in FIGS. 1 to 3 on the left handside of the photograph.

In certain embodiments of the invention, apart from using a bench pressa hammer can be used for flattening tablets/dosage forms. In such aflattening process hammer strikes are manually applied from a directionsubstantially inline with the thickness of e.g. the tablet. The flatnessis then also described in terms of the thickness/smallest diameter ofthe flattened shape compared to the non-flattened shape expressed in %thickness, based on the thickness/smallest diameter of the non-flattenedshape when the initial shape is non spherical, or the % thickness, basedon the non flattened diameter when the initial shape is spherical. Thethickness is measured using a thickness gauge (e.g., digital thicknessgauge or digital caliper).

By contrast, when conducting the breaking strength or tablet hardnesstest as described in Remington's Pharmaceutical Sciences, 18^(th)edition, 1990, Chapter 89 “Oral Solid Dosage Forms”, pages 1633-1665,which is incorporated herein by reference, using the SchleunigerApparatus the tablet/dosage form is put between a pair of flat platesarranged in parallel, and pressed by means of the flat plates, such thatthe force is applied substantially perpendicular to the thickness andsubstantially in line with the diameter of the tablet, thereby reducingthe diameter in that direction. This reduced diameter is described interms of % diameter, based on the diameter of the tablet beforeconducting the breaking strength test. The breaking strength or tablethardness is defined as the force at which the tested tablet/dosage formbreaks. Tablets/dosage forms that do not break, but which are deformeddue to the force applied are considered to be break-resistant at thatparticular force.

A further test to quantify the strength of tablets/dosage forms is theindentation test using a Texture Analyzer, such as the TA-XT2 TextureAnalyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, N.Y.10583). In this method, the tablets/dosage forms are placed on top of astainless stand with slightly concaved surface and subsequentlypenetrated by the descending probe of the Texture Analyzer, such as aTA-8A ⅛ inch diameter stainless steel ball probe. Before starting themeasurement, the tablets are aligned directly under the probe, such thatthe descending probe will penetrate the tablet pivotally, i.e. in thecenter of the tablet, and such that the force of the descending probe isapplied substantially perpendicular to the diameter and substantially inline with the thickness of the tablet. First, the probe of the TextureAnalyzer starts to move towards the tablet sample at the pre-test speed.When the probe contacts the tablet surface and the trigger force set isreached, the probe continues its movement with the test speed andpenetrates the tablet. For each penetration depth of the probe, whichwill hereinafter be referred to as “distance”, the corresponding forceis measured, and the data are collected. When the probe has reached thedesired maximum penetration depth, it changes direction and moves backat the post-test speed, while further data can be collected. Thecracking force is defined to be the force of the first local maximumthat is reached in the corresponding force/distance diagram and iscalculated using for example the Texture Analyzer software “TextureExpert Exceed, Version 2.64 English”. Without wanting to be bound by anytheory, it is believed that at this point, some structural damage to thetablet/dosage form occurs in form of cracking. However, the crackedtablets/dosage forms according to certain embodiments of the presentinvention remain cohesive, as evidenced by the continued resistance tothe descending probe. The corresponding distance at the first localmaximum is hereinafter referred to as the “penetration depth to crack”distance.

For the purposes of certain embodiments of the present invention, theterm “breaking strength” refers to the hardness of the tablets/dosageforms that is preferably measured using the Schleuniger apparatus,whereas the term “cracking force” reflects the strength of thetablets/dosage forms that is preferably measured in the indentation testusing a Texture Analyzer.

A further parameter of the extended release matrix formulations that canbe derived from the indentation test as described above is the work theextended release matrix formulation is subjected to in an indentationtest as described above. The work value corresponds to the integral ofthe force over the distance.

The term “resistant to crushing” is defined for the purposes of certainembodiments of the present invention as referring to dosage forms thatcan at least be flattened with a bench press as described above withoutbreaking to no more than about 60% thickness, preferably no more thanabout 50% thickness, more preferred no more than about 40% thickness,even more preferred no more than about 30% thickness and most preferredno more than about 20% thickness, 10% thickness or 5% thickness.

For the purpose of certain embodiments of the present invention dosageforms are regarded as “resistant to alcohol extraction” when therespective dosage form provides an in-vitro dissolution rate, whenmeasured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C.,characterized by the percent amount of active released at 0.5 hours,preferably at 0.5 and 0.75 hours, more preferred at 0.5, 0.75 and 1hour, even more preferred at 0.5, 0.75, 1 and 1.5 hours and mostpreferred at 0.75, 1, 1.5 and 2 hours of dissolution that deviates nomore than about 20% points or preferably no more than about 15% pointsat each of said time points from the corresponding in-vitro dissolutionrate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C. without ethanol.

The term “tamper resistant” for the purposes of the present inventionrefers to dosage forms which at least provide resistance to crushing orresistance to alcohol extraction, preferably both, as defined above andmay have further tamper resistant characteristics.

For the purpose of the present invention the term “active agent” isdefined as a pharmaceutically active substance which includes withoutlimitation opioid analgesics.

For purposes of the present invention, the term “opioid analgesic”includes single compounds and compositions of compounds selected fromthe group of opioids and which provide an analgesic effect such as onesingle opioid agonist or a combination of opioid agonists, one singlemixed opioid agonist-antagonist or a combination of mixed opioidagonist-antagonists, or one single partial opioid agonist or acombination of partial opioid agonists and combinations of an opioidagonists, mixed opioid agonist-antagonists and partial opioid agonistswith one ore more opioid antagonists, stereoisomers, ether or ester,salts, hydrates and solvates thereof, compositions of any of theforegoing, and the like.

The present invention disclosed herein is specifically meant toencompass the use of the opioid analgesic in form of anypharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts include, but are not limited to,inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like,and metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like.

The opioids used according to the present invention may contain one ormore asymmetric centers and may give rise to enantiomers, diastereomers,or other stereoisomeric forms. The present invention is also meant toencompass the use of all such possible forms as well as their racemicand resolved forms and compositions thereof. When the compoundsdescribed herein contain olefinic double bonds or other centers ofgeometric asymmetry, it is intended to include both E and Z geometricisomers. All tautomers are intended to be encompassed by the presentinvention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms is space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resohltion” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

Opioid agonists useful in the present invention include, but are notlimited to, alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, tramadol,pharmaceutically acceptable salts, hydrates and solvates thereof,mixtures of any of the foregoing, and the like.

Opioid antagonists useful in combination with opioid agonists asdescribed above are e.g. naloxone, naltrexone and nalmephene orpharmaceutically acceptable salts, hydrates and solvates thereof,mixtures of any of the foregoing, and the like.

In certain embodiments e.g. a combination of oxycodone HCl and naloxoneHCl in a ratio of 2:1 is used.

In certain embodiments, the opioid analgesic is selected from codeine,morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone orpharmaceutically acceptable salts, hydrates and solvates thereof,mixtures of any of the foregoing, and the like.

In certain embodiments, the opioid analgesic is oxycodone, hydromorphoneor oxymorphone or a salt thereof such as e.g. the hydrochloride. Thedosage form comprises from about 5 mg to about 500 mg oxycodonehydrochloride, from about 1 mg to about 100 mg hydromorphonehydrochloride or from about 5 mg to about 500 mg oxymorphonehydrochloride. If other salts, derivatives or forms are used, equimolaramounts of any other pharmaceutically acceptable salt or derivative orform including but not limited to hydrates and solvates or the free basemay be used. The dosage form comprises e.g. 5 mg, 7.5 mg, 10 mg, 15 mg,20 mg, 30 mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 120 mg or 160 mgoxycodone hydrochloride or equimolar amounts of any otherpharmaceutically acceptable salt, derivative or form including but notlimited to hydrates and solvates or of the free base. The dosage formcomprises e.g. 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30, mg, 40 mg, 45 mg,60 mg, or 80 mg, 90 mg, 120 mg or 160 mg oxymorphone hydrochloride orequimolar amounts of any other pharmaceutically acceptable salt,derivative or form including but not limited to hydrates and solvates orof the free base. The dosage form comprises e.g. 2 mg, 4 mg, 8 mg, 12mg, 16 mg, 24 mg, 32 mg, 48 mg or 64 mg hydromorphone hydrochloride orequimolar amounts of any other pharmaceutically acceptable salt,derivative or form including but not limited to hydrates and solvates orof the free base.

WO 2005/097801 A1, U.S. Pat. No. 7,129,248 B2 and US 2006/0173029 A1,all of which are hereby incorporated by reference, describe a processfor preparing oxycodone hydrochloride having a 14-hydroxycodeinone levelof less than about 25 ppm, preferably of less than about 15 ppm, lessthan about 10 ppm, or less than about 5 ppm, more preferably of lessthan about 2 ppm, less than about 1 ppm, less than about 0.5 ppm or lessthan about 0.25 ppm.

The term “ppm” as used herein means “parts per million”. Regarding14-hydroxycodeinone, “ppm” means parts per million of14-hydroxycodeinone in a particular sample product. The14-hydroxycodeinone level can be determined by any method known in theart, preferably by HPLC analysis using UV detection.

In certain embodiments of the present invention, wherein the activeagent is oxycodone hydrochloride, oxycodone hydrochloride is used havinga 14-hydroxycodeinone level of less than about 25 ppm, preferably ofless than about 15 ppm, less than about 10 ppm, or less than about 5ppm, more preferably of less than about 2 ppm, less than about 1 ppm,less than about 0.5 ppm or less than about 0.25 ppm.

In certain other embodiments other therapeutically active agents may beused in accordance with the present invention, either in combinationwith opioids or instead of opioids. Examples of such therapeuticallyactive agents include antihistamines (e.g., dimenhydrinate,diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate),non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac,indomethacin, ibuprofen, sulindac, Cox-2 inhibitors) and acetaminophen,anti-emetics (e.g., metoclopramide, methylnaltrexone), anti-epileptics(e.g., phenytoin, meprobmate and nitrazepam), vasodilators (e.g.,nifedipine, papaverine, diltiazem and nicardipine), anti-tussive agentsand expectorants (e.g. codeine phosphate), anti-asthmatics (e.g.theophylline), antacids, anti-spasmodics (e.g. atropine, scopolamine),antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid,bendrofluthiazide), anti-hypotensives (e.g., propranolol, clonidine),antihypertensives (e.g., clonidine, methyldopa), bronchodilatiors (e.g.,albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone),antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics,psychotropics, antidiarrheals, mucolytics, sedatives, decongestants(e.g. pseudoephedrine), laxatives, vitamins, stimulants (includingappetite suppressants such as phenylpropanolamine) and cannabinoids, aswell as pharmaceutically acceptable salts, hydrates, and solvates of thesame.

In certain embodiments, the invention is directed to the use of Cox-2inhibitors as active agents, in combination with opioid analgesics orinstead of opioid analgesics, for example the use of Cox-2 inhibitorssuch as meloxicam(4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide),as disclosed in U.S. Ser. No. 10/056,347 and Ser. No. 11/825,938, whichare hereby incorporated by reference, nabumetone(4-(6-methoxy-2-naphthyl)-2-butanone), as disclosed in U.S. Ser. No.10/056,348, which is hereby incorporated by reference, celecoxib(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide),as disclosed in U.S. Ser. No. 11/698,394, which is hereby incorporatedby reference, nimesulide(N-(4-Nitro-2-phenoxyphenyl)methanesulfonamide), as disclosed in U.S.Ser. No. 10/057,630, which is hereby incorporated by reference, andN-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]methanesulfonamide(T-614), as disclosed in U.S. Ser. No. 10/057,632, which is herebyincorporated by reference.

The present invention is also directed to the dosage forms utilizingactive agents such as for example, benzodiazepines, barbiturates oramphetamines. These may be combined with the respective antagonists.

The term “benzodiazepines” refers to benzodiazepines and drugs that arederivatives of benzodiazepine that are able to depress the centralnervous system. Benzodiazepines include, but are not limited to,alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam,estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam,oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate aswell as pharmaceutically acceptable salts, hydrates, and solvates andmixtures thereof. Benzodiazepine antagonists that can be used in thepresent invention include, but are not limited to, flumazenil as well aspharmaceutically acceptable salts, hydrates, and solvates.

Barbiturates refer to sedative-hypnotic drugs derived from barbituricacid (2,4,6,-trioxohexahydropyrimidine). Barbiturates include, but arenot limited to, amobarbital, aprobarbotal, butabarbital, butalbital,methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital,secobarbital and as well as pharmaceutically acceptable salts, hydrates,and solvates mixtures thereof. Barbiturate antagonists that can be usedin the present invention include, but are not limited to, amphetaminesas well as pharmaceutically acceptable salts, hydrates, and solvates.

Stimulants refer to drugs that stimulate the central nervous system.Stimulants include, but are not limited to, amphetamines, such asamphetamine, dextroamphetamine resin complex, dextroamphetamine,methamphetamine, methylphenidate as well as pharmaceutically acceptablesalts, hydrates, and solvates and mixtures thereof. Stimulantantagonists that can be used in the present invention include, but arenot limited to, benzodiazepines, as well as pharmaceutically acceptablesalts, hydrates, and solvates as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of tablets of Example 7.1 before (left side)and after (right side) the breaking strength test using the SchleunigerModel 6D apparatus.

FIG. 2 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of tablets of Example 7.2 before (left side)and after (right side) the breaking strength test using the SchleunigerModel 6D apparatus.

FIG. 3 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of tablets of Example 7.3 before (left side)and after (right side) the breaking strength test using the SchleunigerModel 6D apparatus.

FIG. 4 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of a tablet of Example 7.1 after flatteningwith a Carver manual bench press (hydraulic unit model #3912).

FIG. 5 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of a tablet of Example 7.2 after flatteningwith a Carver manual bench press (hydraulic unit model #3912).

FIG. 6 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of a tablet of Example 7.3 after flatteningwith a Carver manual bench press (hydraulic unit model #3912).

FIG. 7 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of a tablet of Example 7.1 after 10 manuallyconducted hammer strikes.

FIG. 8 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of a tablet of Example 7.2 after 10 manuallyconducted hammer strikes.

FIG. 9 is a photograph that depicts a top view (view is in line with thethickness of the tablet) of a tablet of Example 7.3 after 10 manuallyconducted hammer strikes.

FIG. 10 is a diagram that depicts the temperature profile of the curingprocess of Example 13.1.

FIG. 11 is a diagram that depicts the temperature profile of the curingprocess of Example 13.2.

FIG. 12 is a diagram that depicts the temperature profile of the curingprocess of Example 13.3.

FIG. 13 is a diagram that depicts the temperature profile of the curingprocess of Example 13.4.

FIG. 14 is a diagram that depicts the temperature profile of the curingprocess of Example 13.5.

FIG. 15 is a diagram that depicts the temperature profile of the curingprocess of Example 14.1.

FIG. 16 is a diagram that depicts the temperature profile of the curingprocess of Example 14.2.

FIG. 17 is a diagram that depicts the temperature profile of the curingprocess of Example 14.3.

FIG. 18 is a diagram that depicts the temperature profile of the curingprocess of Example 14.4.

FIG. 19 is a diagram that depicts the temperature profile of the curingprocess of Example 14.5.

FIG. 20 is a diagram of Example 20 indentation test performed with anExample 13.1 tablet (cured for 30 minutes, uncoated).

FIG. 21 is a diagram of Example 20 indentation test performed with anExample 13.2 tablet (cured for 30 minutes, uncoated).

FIG. 22 is a diagram of Example 20 indentation test performed with anExample 13.3 tablet (cured for 30 minutes, uncoated).

FIG. 23 is a diagram of Example 20 indentation test performed with anExample 13.4 tablet (cured for 30 minutes, uncoated).

FIG. 24 is a diagram of Example 20 indentation test performed with anExample 13.5 tablet (cured for 30 minutes, uncoated).

FIG. 25 is a diagram of Example 20 indentation test performed with anExample 17.1 tablet (cured for 15 minutes at 72° C., coated).

FIG. 26 is a diagram of Example 20 indentation test performed with anExample 18.2 tablet (cured for 15 minutes at 72° C., coated).

FIG. 27 is a diagram of Example 20 indentation test performed with anExample 14.1 tablet (cured for 1 hour, coated).

FIG. 28 is a diagram of Example 20 indentation test performed with anExample 14.2 tablet (cured for 1 hour, coated).

FIG. 29 is a diagram of Example 20 indentation test performed with anExample 14.3 tablet (cured for 1 hour, coated).

FIG. 30 is a diagram of Example 20 indentation test performed with anExample 14.4 tablet (cured for 1 hour, coated).

FIG. 31 is a diagram of Example 20 indentation test performed with anExample 14.5 tablet (cured for 1 hour, coated).

FIG. 32 is a diagram of Example 20 indentation test performed with anExample 16.1 tablet (cured for 15 minutes, coated).

FIG. 33 is a diagram of Example 20 indentation test performed with anExample 16.2 tablet (cured for 15 minutes, coated).

FIG. 34 is a diagram of Example 21 indentation tests performed with anExample 16.1 tablet (cured for 15 minutes, coated) and with a commercialOxycontin™ 60 mg tablet.

FIG. 35 is a diagram of Example 21 indentation tests performed with anExample 16.2 tablet (cured for 15 minutes, coated) and with a commercialOxycontin™ 80 mg tablet.

FIG. 36 shows the mean plasma oxycodone concentration versus timeprofile on linear scale [Population: Full Analysis (Fed State)]according to Example 26.

FIG. 37 shows the mean plasma oxycodone concentration versus timeprofile on log-linear scale [Population: Full Analysis (Fed State)]according to Example 26.

FIG. 38 shows the mean plasma oxycodone concentration versus timeprofile on linear scale [Population: Full Analysis (Fasted State)]according to Example 26.

FIG. 39 shows the mean plasma oxycodone concentration versus timeprofile on log-linear scale [Population: Full Analysis (Fasted State)]according to Example 26.

FIG. 40 shows representative images of crushed OxyContin™ 10 mg andcrushed Example 7.2 tablets, according to Example 27.

FIG. 41 shows representative images of milled Example 7.2 and OxyContin™10 mg tablets before and after 45 minutes of dissolution, according toExample 27.

FIG. 42 shows dissolution profiles of milled Example 7.2 tablets andcrushed OxyContin™ 10 mg tablets, according to Example 27.

FIG. 43 shows particle size distribution graphs of milled tablets(OxyContin™ 10 mg, Example 7.2 and Example 14.5 tablets), according toExample 27.

DETAILED DESCRIPTION

In certain embodiments, the present invention is directed to a processof preparing a solid oral extended release pharmaceutical dosage form,comprising at least the steps of:

-   -   (a) combining at least        -   (1) at least one polyethylene oxide having, based on            rheological measurements, an approximate molecular weight of            at least 1,000,000, and        -   (2) at least one active agent,        -   to form a composition;    -   (b) shaping the composition to form an extended release matrix        formulation; and    -   (c) curing said extended release matrix formulation comprising        at least a curing step of subjecting the extended release matrix        formulation to a temperature which is at least the softening        temperature of said polyethylene oxide for a time period of at        least about 1 minute.        Preferably, the curing is conducted at atmospheric pressure.

In a certain embodiment the present invention concerns a process ofpreparing a solid oral extended release pharmaceutical dosage form,comprising at least the steps of:

-   -   (a) combining at least        -   (1) at least one polyethylene oxide having, based on            rheological measurements, an molecular weight of at least            1,000,000; and        -   (2) at least one active agent,        -   to form a composition;    -   (b) shaping the composition to form an extended release matrix        formulation; and    -   (c) curing said extended release matrix formulation comprising        at least a curing step of subjecting the extended release matrix        formulation to a temperature which is at least the softening        temperature of said polyethylene oxide for a time period of at        least 5 minutes. Preferably, the curing is conducted at        atmospheric pressure.

In certain embodiments, the present invention is directed to a processof preparing a solid oral extended release pharmaceutical dosage form,comprising at least the steps of:

-   -   (a) combining at least        -   (1) at least one polyethylene oxide having, based on            rheological measurements, an approximate molecular weight of            at least 1,000,000, and        -   (2) at least one active agent,        -   to form a composition;    -   (b) shaping the composition to form an extended release matrix        formulation; and    -   (c) curing said extended release matrix formulation comprising        at least a curing step wherein said polyethylene oxide at least        partially melts.        Preferably, the curing is conducted at atmospheric pressure.

In certain embodiments the composition is shaped in step b) to form anextended release matrix formulation in the form of tablet. For shapingthe extended release matrix formulation in the form of tablet a directcompression process can be used. Direct compression is an efficient andsimple process for shaping tablets by avoiding process steps like wetgranulation. However, any other process for manufacturing tablets asknown in the art may be used, such as wet granulation and subsequentcompression of the granules to form tablets.

In one embodiment, the curing of the extended release matrix formulationin step c) comprises at least a curing step wherein the high molecularweight polyethylene oxide in the extended release matrix formulation atleast partially melts. For example, at least about 20% or at least about30% of the high molecular weight polyethylene oxide in the extendedrelease matrix formulation melts. Preferably, at least about 40% or atleast about 50%, more preferably at least about 60%, at least about 75%or at least about 90% of the high molecular weight polyethylene oxide inthe extended release matrix formulation melts. In a preferredembodiment, about 100% of the high molecular weight polyethylene oxidemelts.

In other embodiments, the curing of the extended release matrixformulation in step c) comprises at least a curing step wherein theextended release matrix formulation is subjected to an elevatedtemperature for a certain period of time. In such embodiments, thetemperature employed in step c), i.e. the curing temperature, is atleast as high as the softening temperature of the high molecular weightpolyethylene oxide. Without wanting to be bound to any theory it isbelieved that the curing at a temperature that is at least as high asthe softening temperature of the high molecular weight polyethyleneoxide causes the polyethylene oxide particles to at least adhere to eachother or even to fuse. According to some embodiments the curingtemperature is at least about 60° C. or at least about 62° C. or rangesfrom about 62° C. to about 90° C. or from about 62° C. to about 85° C.or from about 62° C. to about 80° C. or from about 65° C. to about 90°C. or from about 65° C. to about 85° C. or from about 65° C. to about80° C. The curing temperature preferably ranges from about 68° C. toabout 90° C. or from about 68° C. to about 85° C. or from about 68° C.to about 80° C. more preferably from about 70° C. to about 90° C. orfrom about 70° C. to about 85° C. or from about 70° C. to about 80° C.,most preferably from about 72° C. to about 90° C. or from about 72° C.to about 85° C. or from about 72° C. to about 80° C. The curingtemperature may be at least about 60° C. or at least about 62° C., butless than about 90° C. or less than about 80° C. Preferably, it is inthe range of from about 62° C. to about 72° C., in particular from about68° C. to about 72° C. Preferably, the curing temperature is at least ashigh as the lower limit of the softening temperature range of the highmolecular weight polyethylene oxide or at least about 62° C. or at leastabout 68° C. More preferably, the curing temperature is within thesoftening temperature range of the high molecular weight polyethyleneoxide or at least about 70° C. Even more preferably, the curingtemperature is at least as high as the upper limit of the softeningtemperature range of the high molecular weight polyethylene oxide or atleast about 72° C. In an alternative embodiment, the curing temperatureis higher than the upper limit of the softening temperature range of thehigh molecular weight polyethylene oxide, for example the curingtemperature is at least about 75° C. or at least about 80° C.

In those embodiments where the curing of the extended release matrixformulation in step c) comprises at least a curing step wherein theextended release matrix formulation is subjected to an elevatedtemperature for a certain period of time, this period of time ishereinafter referred to as the curing time. For the measurement of thecuring time a starting point and an end point of the curing step isdefined. For the purposes of the present invention, the starting pointof the curing step is defined to be the point in time when the curingtemperature is reached.

In certain embodiments, the temperature profile during the curing stepshows a plateau-like form between the starting point and the end pointof the curing. In such embodiments the end point of the curing step isdefined to be the point in time when the heating is stopped or at leastreduced, e.g. by terminating or reducing the heating and/or by startinga subsequent cooling step, and the temperature subsequently drops belowthe curing temperature by more than about 10° C. and/or below the lowerlimit of the softening temperature range of high molecular weightpolyethylene oxide, for example below about 62° C. When the curingtemperature is reached and the curing step is thus started, deviationsfrom the curing temperature in the course of the curing step can occur.Such deviations are tolerated as long as they do not exceed a value ofabout ±10° C., preferably about ±6° C., and more preferably about ±3° C.For example, if a curing temperature of at least about 75° C. is to bemaintained, the measured temperature may temporarily increase to a valueof about 85° C., preferably about 81° C. and more preferably about 78°C., and the measured temperature may also temporarily drop down to avalue of about 65° C., preferably about 69° C. and more preferably about72° C. In the cases of a larger decrease of the temperature and/or inthe case that the temperature drops below the lower limit of thesoftening temperature range of high molecular weight polyethylene oxide,for example below about 62° C., the curing step is discontinued, i.e. anend point is reached. Curing can be restarted by again reaching thecuring temperature.

In other embodiments, the temperature profile during the curing stepshows a parabolic or triangular form between the starting point and theend point of the curing. This means that after the starting point, i.e.the point in time when the curing temperature is reached, thetemperature further increases to reach a maximum, and then decreases. Insuch embodiments, the end point of the curing step is defined to be thepoint in time when the temperature drops below the curing temperature.

In this context, it has to be noted that depending on the apparatus usedfor the curing, which will hereinafter be called curing device,different kinds of temperatures within the curing device can be measuredto characterize the curing temperature.

In certain embodiments, the curing step may take place in an oven. Insuch embodiments, the temperature inside the oven is measured. Basedthereon, when the curing step takes place in an oven, the curingtemperature is defined to be the target inside temperature of the ovenand the starting point of the curing step is defined to be the point intime when the inside temperature of the oven reaches the curingtemperature. The end point of the curing step is defined to be (1) thepoint in time when the heating is stopped or at least reduced and thetemperature inside the oven subsequently drops below the curingtemperature by more than about 10° C. and/or below the lower limit ofthe softening temperature range of high molecular weight polyethyleneoxide, for example below about 62° C., in a plateau-like temperatureprofile or (2) the point in time when the temperature inside the ovendrops below the curing temperature in a parabolic or triangulartemperature profile. Preferably, the curing step starts when thetemperature inside the oven reaches a curing temperature of at leastabout 62° C., at least about 68° C. or at least about 70° C., morepreferably of at least about 72° C. or at least about 75° C. Inpreferred embodiments, the temperature profile during the curing stepshows a plateau-like form, wherein the curing temperature, i.e. theinside temperature of the oven, is preferably at least about 68° C., forexample about 70° C. or about 72° C. or about 73° C., or lies within arange of from about 70° C. to about 75° C., and the curing time ispreferably in the range of from about 30 minutes to about 20 hours, morepreferably from about 30 minutes to about 15 hours, or from about 30minutes to about 4 hours or from about 30 minutes to about 2 hours. Mostpreferably, the curing time is in the range of from about 30 minutes toabout 90 minutes.

In certain other embodiments, the curing takes place in curing devicesthat are heated by an air flow and comprise a heated air supply (inlet)and an exhaust, like for example a coating pan or fluidized bed. Suchcuring devices will hereinafter be called convection curing devices. Insuch curing devices, it is possible to measure the temperature of theinlet air, i.e. the temperature of the heated air entering theconvection curing device and/or the temperature of the exhaust air, i.e.the temperature of the air leaving the convection curing device. It isalso possible to determine or at least estimate the temperature of theformulations inside the convection curing device during the curing step,e.g. by using infrared temperature measurement instruments, such as anIR gun, or by measuring the temperature using a temperature probe thatwas placed inside the curing device near the extended release matrixformulations. Based thereon, when the curing step takes place in aconvection curing device, the curing temperature can be defined and thecuring time can be measured as the following.

In one embodiment, wherein the curing time is measured according tomethod 1, the curing temperature is defined to be the target inlet airtemperature and the starting point of the curing step is defined to bethe point in time when the inlet air temperature reaches the curingtemperature. The end point of the curing step is defined to be (1) thepoint in time when the heating is stopped or at least reduced and theinlet air temperature subsequently drops below the curing temperature bymore than about 10° C. and/or below the lower limit of the softeningtemperature range of high molecular weight polyethylene oxide, forexample below about 62° C., in a plateau-like temperature profile or (2)the point in time when the inlet air temperature drops below the curingtemperature in a parabolic or triangular temperature profile.Preferably, the curing step starts according to method 1, when the inletair temperature reaches a curing temperature of at least about 62° C.,at least about 68° C. or at least about 70° C., more preferably, of atleast about 72° C. or at least about 75° C. In a preferred embodiment,the temperature profile during the curing step shows a plateau-likeform, wherein the curing temperature, i.e. the target inlet airtemperature, is preferably at least about 72° C., for example about 75°C., and the curing time which is measured according to method 1 ispreferably in the range of from about 15 minutes to about 2 hours, forexample about 30 minutes or about 1 hour.

In another embodiment, wherein the curing time is measured according tomethod 2, the curing temperature is defined to be the target exhaust airtemperature and the starting point of the curing step is defined to bethe point in time when the exhaust air temperature reaches the curingtemperature. The end point of the curing step is defined to be (1) thepoint in time when the heating is stopped or at least reduced and theexhaust air temperature subsequently drops below the curing temperatureby more than about 10° C. and/or below the lower limit of the softeningtemperature range of high molecular weight polyethylene oxide, forexample below about 62° C., in a plateau-like temperature profile or (2)the point in time when the exhaust air temperature drops below thecuring temperature in a parabolic or triangular temperature profile.Preferably, the curing step starts according to method 2, when theexhaust air temperature reaches a curing temperature of at least about62° C., at least about 68° C. or at least about 70° C., more preferably,of at least about 72° C. or at least about 75° C. In preferredembodiments, the temperature profile during the curing step shows aplateau-like form, wherein the curing temperature, i.e. the targetexhaust air temperature, is preferably at least about 68° C., at leastabout 70° C. or at least about 72° C., for example the target exhaustair temperature is about 68° C., about 70° C., about 72° C., about 75°C. or about 78° C., and the curing time which is measured according tomethod 2 is preferably in the range of from about 1 minute to about 2hours, preferably from about 5 minutes to about 90 minutes, for examplethe curing time is about 5 minutes, about 10 minutes, about 15 minutes,about 30 minutes, about 60 minutes, about 70 minutes, about 75 minutesor about 90 minutes. In a more preferred embodiment, the curing timewhich is measured according to method 2 is in the range of from about 15minutes to about 1 hour.

In a further embodiment, wherein the curing time is measured accordingto method 3, the curing temperature is defined to be the targettemperature of the extended release matrix formulations and the startingpoint of the curing step is defined to be the point in time when thetemperature of the extended release matrix formulations, which can bemeasured for example by an IR gun, reaches the curing temperature. Theend point of the curing step is defined to be (1) the point in time whenthe heating is stopped or at least reduced and the temperature of theextended release matrix formulations subsequently drops below the curingtemperature by more than about 10° C. and/or below the lower limit ofthe softening temperature range of high molecular weight polyethyleneoxide, for example below about 62° C., in a plateau-like temperatureprofile or (2) the point in time when the temperature of the extendedrelease matrix formulations drops below the curing temperature in aparabolic or triangular temperature profile. Preferably, the curing stepstarts according to method 3, when the temperature of the extendedrelease matrix formulations reaches a curing temperature of at leastabout 62° C., at least about 68° C. or at least about 70° C., morepreferably, of at least about 72° C. or at least about 75° C.

In still another embodiment, wherein the curing time is measuredaccording to method 4, the curing temperature is defined to be thetarget temperature measured using a temperature probe, such as a wirethermocouple, that was placed inside the curing device near the extendedrelease matrix formulations and the starting point of the curing step isdefined to be the point in time when the temperature measured using atemperature probe that was placed inside the curing device near theextended release matrix formulations reaches the curing temperature. Theend point of the curing step is defined to be (1) the point in time whenthe heating is stopped or at least reduced and the temperature measuredusing the temperature probe subsequently drops below the curingtemperature by more than about 10° C. and/or below the lower limit ofthe softening temperature range of high molecular weight polyethyleneoxide, for example below about 62° C., in a plateau-like temperatureprofile or (2) the point in time when the temperature measured using thetemperature probe drops below the curing temperature in a parabolic ortriangular temperature profile. Preferably, the curing step startsaccording to method 4, when the temperature measured using a temperatureprobe that was placed inside the curing device near the extended releasematrix formulations reaches a curing temperature of at least about 62°C., at least about 68° C. or at least about 70° C., more preferably, ofat least about 72° C. or at least about 75° C. In a preferredembodiment, the temperature profile during the curing step shows aplateau-like form, wherein the curing temperature, i.e. the targettemperature measured using a temperature probe that was placed insidethe curing device near the extended release matrix formulations, ispreferably at least about 68° C., for example it is about 70° C., andthe curing time which is measured according to method 4 is preferably inthe range of from about 15 minutes to about 2 hours, for example thecuring time is about 60 minutes or about 90 minutes.

If curing takes place in a convection curing device, the curing time canbe measured by any one of methods 1, 2, 3 or 4. In a preferredembodiment, the curing time is measured according to method 2.

In certain embodiments, the curing temperature is defined as a targettemperature range, for example the curing temperature is defined as atarget inlet air temperature range or a target exhaust air temperaturerange. In such embodiments, the starting point of the curing step isdefined to be the point in time when the lower limit of the targettemperature range is reached, and the end point of the curing step isdefined to be the point in time when the heating is stopped or at leastreduced, and the temperature subsequently drops below the lower limit ofthe target temperature range by more than about 10° C. and/or below thelower limit of the softening temperature range of high molecular weightpolyethylene oxide, for example below about 62° C.

The curing time, i.e. the time period the extended release matrixformulation is subjected to the curing temperature, which can forexample be measured according to methods 1, 2, 3 and 4 as describedabove, is at least about 1 minute or at least about 5 minutes. Thecuring time may vary from about 1 minute to about 24 hours or from about5 minutes to about 20 hours or from about 10 minutes to about 15 hoursor from about 15 minutes to about 10 hours or from about 30 minutes toabout 5 hours depending on the specific composition and on theformulation and the curing temperature. The parameter of thecomposition, the curing time and the curing temperature are chosen toachieve the tamper resistance as described herein. According to certainembodiments the curing time varies from about 15 minutes to about 30minutes. According to further embodiments wherein the curing temperatureis at least about 60° C. or at least about 62° C., preferably at leastabout 68° C., at least about 70° C., at least about 72° C. or at leastabout 75° C. or varies from about 62° C. to about 85° C. or from about65° C. to about 85° C. the curing time is preferably at least about 15minutes, at least about 30 minutes, at least about 60 minutes, at leastabout 75 minutes, at least about 90 minutes or about 120 minutes. Inpreferred embodiments, wherein the curing temperature is for example atleast about 62° C., at least about 68° C. or at least about 70° C.,preferably at least about 72° C. or at least about 75° C., or rangesfrom about 62° C. to about 80° C., from about 65° C. to about 80° C.,from about 68° C. to about 80° C., from about 70° C. to about 80° C. orfrom about 72° C. to about 80° C., the curing time is preferably atleast about 1 minute or at least about 5 minutes. More preferably, thecuring time is at least about 10 minutes, at least about 15 minutes orat least about 30 minutes. In certain such embodiments, the curing timecan be chosen to be as short as possible while still achieving thedesired tamper resistance. For example, the curing time preferably doesnot exceed about 5 hours, more preferably it does not exceed about 3hours and most preferably it does not exceed about 2 hours. Preferably,the curing time is in the range of from about 1 minute to about 5 hours,from about 5 minutes to about 3 hours, from about 15 minutes to about 2hours or from about 15 minutes to about 1 hour. Any combination of thecuring temperatures and the curing times as disclosed herein lies withinthe scope of the present invention.

In certain embodiments, the composition is only subjected to the curingtemperature until the high molecular weight polyethylene oxide presentin the extended release matrix formulation has reached its softeningtemperature and/or at least partially melts. In certain suchembodiments, the curing time may be less than about 5 minutes, forexample the curing time may vary from about 0 minutes to about 3 hoursor from about 1 minute to about 2 hours or from about 2 minutes to about1 hour. Instant curing is possible by choosing a curing device whichallows for an instant heating of the high molecular weight polyethyleneoxide in the extended release matrix formulation to at least itssoftening temperature, so that the high molecular weight polyethyleneoxide at least partially melts. Such curing devices are for examplemicrowave ovens, ultrasound devices, light irradiation apparatus such asUV-irradiation apparatus, ultra-high frequency (UHF) fields or anymethod known to the person skilled in the art.

The skilled person is aware that the size of the extended release matrixformulation may determine the required curing time and curingtemperature to achieve the desired tamper resistance. Without wanting tobe bound by any theory, it is believed that in the case of a largeextended release matrix formulation, such as a large tablet, a longercuring time is necessary to conduct the heat into the interior of theformulation than in the case of a corresponding formulation with smallersize. Higher temperature increases the thermal conductivity rate andthereby decreases the required curing time.

The curing step c) may take place in an oven. Advantageously, the curingstep c) takes place in a bed of free flowing extended release matrixformulations as e.g. in a coating pan. The coating pan allows anefficient batch wise curing step which can subsequently be followed by acoating step without the need to transfer the dosage forms, e.g. thetablets. Such a process may comprise the steps of:

-   -   (a) combining at least        -   (1) at least one polyethylene oxide having, based on            rheological measurements, an approximate molecular weight of            at least 1,000,000, and        -   (2) at least one active agent,        -   to form a composition;    -   (b) shaping said composition to form the extended release matrix        formulation in the form of a tablet by direct compression;    -   (c) curing said tablet by        -   subjecting a bed of free flowing tablets to a temperature            from about 62° C. to about 90° C., preferably from about            70° C. to about 90° C. for a time period of at least about 1            minute or at least about 5 minutes, preferably of at least            about 30 minutes, in a coating pan and        -   subsequently cooling the bed of free flowing tablets to a            temperature of below about 50° C.;        -   and subsequently    -   (d) coating the dosage form in said coating pan.

In certain embodiments, an additional curing step can follow after stepd) of coating the dosage form. An additional curing step can beperformed as described for curing step c). In certain such embodiments,the curing temperature of the additional curing step is preferably atleast about 70° C., at least about 72° C. or at least about 75° C., andthe curing time is preferably in the range of from about 15 minutes toabout 1 hour, for example about 30 minutes.

In certain embodiments an antioxidant, e.g. BHT (butylatedhydroxytoluene) is added to the composition.

In certain embodiments, the curing step c) leads to a decrease in thedensity of the extended release matrix formulation, such that thedensity of the cured extended release matrix formulation is lower thanthe density of the extended release matrix formulation prior to thecuring step c). Preferably, the density of the cured extended releasematrix formulation in comparison to the density of the uncured extendedrelease matrix formulation decreases by at least about 0.5%. Morepreferably, the density of the cured extended release matrix formulationin comparison to the density of the uncured extended release matrixformulation decreases by at least about 0.7%, at least about 0.8%, atleast about 1.0%, at least about 2.0% or at least about 2.5%. Withoutwanting to be bound by any theory, it is believed that the extendedrelease matrix formulation, due to the absence of elevated pressureduring the curing step c), expands, resulting in a density decrease.

According to a further aspect of the invention, the density of theextended release matrix formulation in the solid oral extended releasepharmaceutical dosage form, preferably in a dosage form containingoxycodone HCl as active agent, is equal to or less than about 1.20g/cm³. Preferably, it is equal to or less than about 1.19 g/cm³, equalto or less than about 1.18 g/cm³, or equal to or less than about 1.17g/cm³. For example, the density of the extended release matrixformulation is in the range of from about 1.10 g/cm³ to about 1.20g/cm³, from about 1.11 g/cm³ to about 1.20 g/cm³, or from about 1.11g/cm³ to about 1.19 g/cm³. Preferably it is in the range of from about1.12 g/cm³ to about 1.19 g/cm³ or from about 1.13 g/cm³ to about 1.19g/cm³, more preferably from about 1.13 g/cm³ to about 1.18 g/cm³.

The density of the extended release matrix formulation is preferablydetermined by Archimedes Principle using a liquid of known density (ρ₀).

The extended release matrix formulation is first weighed in air and thenimmersed in a liquid and weighed. From these two weights, the density ofthe extended release matrix formulation ρ can be determined by theequation:

$\rho = {\frac{A}{A - B} \cdot \rho_{0}}$

wherein ρ is the density of the extended release matrix formulation, Ais the weight of the extended release matrix formulation in air, B isthe weight of the extended release matrix formulation when immersed in aliquid and ρ₀ is the density of the liquid at a given temperature. Asuitable liquid of known density ρ₀ is for example hexane.

Preferably, the density of an extended release matrix formulation ismeasured using a Top-loading Mettler Toledo balance Model #AB135-S/FACT, Serial #1127430072 and a density determination kit 33360.Preferably, hexane is used as liquid of known density ρ₀.

The density values throughout this document correspond to the density ofthe extended release matrix formulation at room temperature.

The density of the extended release matrix formulation preferably refersto the density of the uncoated formulation, for example to the densityof a core tablet. In those embodiments, wherein the extended releasematrix formulation is coated, for example wherein the extended releasematrix formulation is subjected to a coating step d) after the curingstep c), the density of the extended release matrix formulation ispreferably measured prior to performing the coating step, or by removingthe coating from a coated extended release matrix formulation andsubsequently measuring the density of the uncoated extended releasematrix formulation.

In the above described embodiments high molecular weight polyethyleneoxide having, based on rheological measurements, an approximatemolecular weight of from 2,000,000 to 15,000,000 or from 2,000,000 to8,000,000 may be used. In particular polyethylene oxides having, basedon rheological measurements, an approximate molecular weight of2,000,000, 4,000,000, 7,000,000 or 8,000,000 may be used. In particularpolyethylene oxides having, based on rheological measurements, anapproximate molecular weight of 4,000,000, may be used.

In embodiments wherein the composition further comprises at least onelow molecular weight polyethylene oxide is used polyethylene oxideshaving, based on rheological measurements, an approximate molecularweight of less than 1,000,000, such as polyethylene oxides having, basedon rheological measurements, an approximate molecular weight of from100,000 to 900,000 may be used. The addition of such low molecularweight polyethylene oxides may be used to specifically tailor therelease rate such as enhance the release rate of a formulation thatotherwise provides a release rate to slow for the specific purpose. Insuch embodiments at least one polyethylene oxide having, based onrheological measurements, an approximate molecular weight of 100,000 maybe used.

In certain such embodiments the composition comprises at least onepolyethylene oxide having, based on rheological measurements, anapproximate molecular weight of at least 1,000,000 and at least onepolyethylene oxide having, based on rheological measurements, anapproximate molecular weight of less than 1,000,000, wherein thecomposition comprises at least about 10% (by wt) or at least about 20%(by wt) of the polyethylene oxide having, based on rheologicalmeasurements, an approximate molecular weight of less than 1,000,000. Incertain such embodiments the curing temperature is less than about 80°C. or even less than about 77° C.

In certain embodiments the overall content of polyethylene oxide in thecomposition is at least about 80% (by wt). Without wanting to be boundto any theory it is believed that high contents of polyethylene oxideprovide for the tamper resistance as described herein, such as thebreaking strength and the resistance to alcohol extraction. According tocertain such embodiments the active agent is oxycodone hydrochloride andthe composition comprises more than about 5% (by wt) of the oxycodonehydrochloride.

In certain such embodiments the content in the composition of the atleast one polyethylene oxide having, based on rheological measurements,an approximate molecular weight of at least 1,000,000 is at least about80% (by wt). In certain embodiments the content in the composition ofthe at least one polyethylene oxide having, based on rheologicalmeasurements, an approximate molecular weight of at least 1,000,000 isat least about 85% or at least about 90% (by wt). In such embodiments apolyethylene oxide having, based on rheological measurements, anapproximate molecular weight of at least 4,000,000 or at least 7,000,000may be employed. In certain such embodiments the active agent isoxycodone hydrochloride or hydromorphone hydrochloride, although otheractive agents can also be used according to this aspect of theinvention, and the composition comprises more than about 5% (by wt)oxycodone hydrochloride or hydromorphone hydrochloride.

In certain embodiments wherein the amount of drug in the composition isat least about 20% (by wt) the polyethylene oxide content may be as lowas about 75% (by wt). In another embodiment, wherein the amount of drugin the composition is in the range of from about 25% (by wt) to about35% (by wt), the polyethylene oxide content may be in the range of fromabout 65% (by wt) to about 75% (by wt). For example, in embodimentswherein the amount of drug in the composition is about 32% (by wt) thepolyethylene oxide content may be about 67% (by wt).

In certain embodiments of the invention magnesium stearate is addedduring or after the curing process/curing step in order to avoid thatthe tablets stick together. In certain such embodiments the magnesiumstearate is added at the end of the curing process/curing step beforecooling the tablets or during the cooling of the tablets. Otheranti-tacking agents that could be used would be talc, silica, fumedsilica, colloidal silica dioxide, calcium stearate, carnauba wax, longchain fatty alcohols and waxes, such as stearic acid and stearylalcohol, mineral oil, paraffin, micro crystalline cellulose, glycerin,propylene glycol, and polyethylene glycol. Additionally or alternativelythe coating can be started at the high temperature.

In certain embodiments, wherein curing step c) is carried out in acoating pan, sticking of tablets can be avoided or sticking tablets canbe separated by increasing the pan speed during the curing step or afterthe curing step, in the latter case for example before or during thecooling of the tablets. The pan speed is increased up to a speed whereall tablets are separated or no sticking occurs.

In certain embodiments of the invention, an initial film coating or afraction of a film coating is applied prior to performing curing stepc). This film coating provides an “overcoat” for the extended releasematrix formulations or tablets to function as an anti-tacking agent,i.e. in order to avoid that the formulations or tablets stick together.In certain such embodiments the film coating which is applied prior tothe curing step is an Opadry film coating. After the curing step c), afurther film coating step can be performed.

The present invention encompasses also any solid oral extended releasepharmaceutical dosage form obtainable by a process according to anyprocess as described above.

Independently, the present invention is also directed to solid oralextended release pharmaceutical dosage forms.

In certain embodiments the invention is directed to solid oral extendedrelease pharmaceutical dosage forms comprising an extended releasematrix formulation comprising an active agent in the form of a tablet ormulti particulates, wherein the tablet or the individual multiparticulates can at least be flattened without breaking, characterizedby a thickness of the tablet or of the individual multi particulateafter the flattening which corresponds to no more than about 60% of thethickness of the tablet or the individual multi particulate beforeflattening, and wherein said flattened tablet or the flattened multiparticulates provide an in-vitro dissolution rate, when measured in aUSP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37° C., characterized by the percent amount ofactive released at 0.5 hours or at 0.5 and 0.75 hours, or at 0.5, 0.75and 1 hours, or at 0.5, 0.75, 1 and 1.5 hours or at 0.5, 0.75, 1, 1.5and 2 hours of dissolution that deviates no more than about 20% pointsat each of said time points from the corresponding in-vitro dissolutionrate of a non-flattened reference tablet or reference multiparticulates.

In certain such embodiments the tablet or the individual multiparticulates can at least be flattened without breaking, characterizedby a thickness of the tablet or the individual multi particulate afterthe flattening which corresponds to no more than about 50%, or no morethan about 40%, or no more than about 30%, or no more than about 20%, orno more than about 16% of the thickness of the tablet or the individualmulti particulate before flattening, and wherein said flattened tabletor the flattened multi particulates provide an in-vitro dissolutionrate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C., characterizedby the percent amount of active released at 0.5 hours or at 0.5 and 0.75hours, or at 0.5, 0.75 and 1 hours, or at 0.5, 0.75, 1 and 1.5 hours orat 0.5, 0.75, 1, 1.5 and 2 hours of dissolution that deviates no morethan about 20% points or no more than about 15% points at each of saidtime points from the corresponding in-vitro dissolution rate of anon-flattened reference tablet or reference multi particulates.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation comprising an active agent in the form of atablet or multi particulates,

wherein the tablet or the individual multi particulates can at least beflattened without breaking, characterized by a thickness of the tabletor of the individual multi particulate after the flattening whichcorresponds to no more than about 60% of the thickness of the tablet orthe individual multi particulate before flattening, and wherein saidflattened tablet or the flattened multi particulates and thenon-flattened reference tablet or reference multi particulates providean in-vitro dissolution rate, which when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C., is between about 5 and about 40% (by wt) active agentreleased after 0.5 hours.

In certain such embodiments, the tablet or the individual multiparticulates can at least be flattened without breaking, characterizedby a thickness of the tablet or of the individual multi particulateafter the flattening which corresponds to no more than about 50%, or nomore than about 40%, or no more than about 30%, or no more than about20%, or no more than about 16% of the thickness of the tablet or theindividual multi particulate before flattening, and wherein saidflattened tablet or the flattened multi particulates and thenon-flattened reference tablet or reference multi particulates providean in-vitro dissolution rate, which when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C., is between about 5 and about 40% (by wt) active agentreleased after 0.5 hours or is between about 5 and about 30% (by wt)active agent released after 0.5 hours or is between about 5 and about20% (by wt) active agent released after 0.5 hours or is between about 10and about 18% (by wt) active agent released after 0.5 hours.

In certain embodiments the invention is directed to a solid oralextended release pharmaceutical dosage form comprising an extendedrelease matrix formulation comprising an active agent in the form of atablet or multi particulates, wherein the tablet or the individual multiparticulates can at least be flattened without breaking, characterizedby a thickness of the tablet or the individual multi particulate afterthe flattening which corresponds to no more than about 60% of thethickness of the tablet or the individual multi particulate beforeflattening, and wherein the flattened or non flattened tablet or theflattened or non flattened multi particulates provide an in-vitrodissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpmin 900 ml simulated gastric fluid without enzymes (SGF) comprising 40%ethanol at 37° C., characterized by the percent amount of activereleased at 0.5 hours or at 0.5 and 0.75 hours, or at 0.5, 0.75 and 1hours, or at 0.5, 0.75, 1 and 1.5 hours or at 0.5, 0.75, 1, 1.5 and 2hours of dissolution that deviates no more than about 20% points at eachtime point from the corresponding in-vitro dissolution rate measured ina USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37° C. without ethanol, using a flattened andnon flattened reference tablet or flattened and non flattened referencemulti particulates, respectively.

In certain such embodiments the tablet or the multi particulates can atleast be flattened without breaking, characterized by a thickness of thetablet or the individual multi particulate after the flattening whichcorresponds to no more than about 60%, or no more than about 50%, or nomore than about 40%, or no more than about 30%, or no more than about20%, or no more than about 16% of the thickness of the tablet or theindividual multi particulate before flattening, and wherein theflattened or non flattened tablet or the individual multi particulatesprovide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) comprising 40% ethanol at 37° C., characterized by the percentamount of active released at 0.5 hours or at 0.5 and 0.75 hours, or at0.5, 0.75 and 1 hours, or at 0.5, 0.75, 1 and 1.5 hours or at 0.5, 0.75,1, 1.5 and 2 hours of dissolution that deviates no more than about 20%points or no more than about 15% points at each of said time points fromthe corresponding in-vitro dissolution rate measured in a USP Apparatus1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. without ethanol, using a flattened and a non flattenedreference tablet or reference multi particulates, respectively.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation comprising an active agent in the form of atablet or multi particulates,

wherein the tablet or the individual multi particulates can at least beflattened without breaking, characterized by a thickness of the tabletor the individual multi particulate after the flattening whichcorresponds to no more than about 60% of the thickness of the tablet orthe individual multi particulate before flattening, and wherein theflattened or non flattened tablet or the flattened or non flattenedmulti particulates provide an in-vitro dissolution rate, which whenmeasured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) comprising 40% or 0% ethanol at 37°C., is between about 5 and about 40% (by wt) active agent released after0.5 hours.

In certain such embodiments, the tablet or the individual multiparticulates can at least be flattened without breaking, characterizedby a thickness of the tablet or the individual multi particulate afterthe flattening which corresponds to no more than about 50%, or no morethan about 40%, or no more than about 30%, or no more than about 20%, orno more than about 16% of the thickness of the tablet or the individualmulti particulate before flattening, and wherein the flattened or nonflattened tablet or the flattened or non flattened multi particulatesprovide an in-vitro dissolution rate, which when measured in a USPApparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) comprising 40% or 0% ethanol at 37° C., is betweenabout 5 and about 40% (by wt) active agent released after 0.5 hours oris between about 5 and about 30% (by wt) active agent released after 0.5hours or is between about 5 and about 20% (by wt) active agent releasedafter 0.5 hours or is between about 10 and about 18% (by wt) activeagent released after 0.5 hours.

Such dosage forms may be prepared as described above.

In certain embodiments the invention is directed to a solid oralextended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) at least one active agent, preferably selected from opioid        analgesics; and        wherein the composition comprises at least about 80% (by wt)        polyethylene oxide. The composition may also comprise at least        about 85 or 90% (by wt) polyethylene oxide. According to certain        such embodiments wherein the composition comprises at least        about 80% (by wt) polyethylene oxide, the active agent is        oxycodone hydrochloride or hydromorphone hydrochloride and the        composition comprises more than about 5% (by wt) of the        oxycodone hydrochloride or hydromorphone hydrochloride.

In certain such embodiments the composition comprises at least about 80%(by wt) polyethylene oxide having, based on rheological measurements, anapproximate molecular weight of at least 1,000,000.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 10 mg oxycodone hydrochloride; and

wherein the composition comprises at least about 85% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 15 mg or 20 mg oxycodone hydrochloride; and

wherein the composition comprises at least about 80% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 40 mg oxycodone hydrochloride; and

wherein the composition comprises at least about 65% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 60 mg or 80 mg oxycodone hydrochloride; and

wherein the composition comprises at least about 60% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 8 mg hydromorphone hydrochloride; and

wherein the composition comprises at least about 94% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 12 mg hydromorphone hydrochloride; and

wherein the composition comprises at least about 92% (by wt)polyethylene oxide.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) 32 mg hydromorphone hydrochloride; and

wherein the composition comprises at least about 90% (by wt)polyethylene oxide.

In certain embodiments the present invention is directed to a solid oralextended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising a composition comprising at least:

-   -   (1) at least one active agent, preferably selected from opioid        analgesics;    -   (2) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (3) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of less than        1,000,000. In certain such embodiments the composition comprises        at least about 80% (by wt) of polyethylene oxide. The        composition may also comprise at least about 85 or 90% (by wt)        polyethylene oxide. According to certain such embodiments        wherein the composition comprises at least about 80% (by wt)        polyethylene oxide, the active agent is oxycodone hydrochloride        or hydromorphone hydrochloride and the composition comprises        more than about 5% (by wt) of the oxycodone hydrochloride or the        hydromorphone hydrochloride. The composition may also comprise        15 to 30% (by wt) of polyethylene oxide having, based on        rheological measurements, a molecular weight of at least        1,000,000; and 65 to 80% (by wt) polyethylene oxide having,        based on rheological measurements, a molecular weight of less        than 1,000,000, or the composition may comprise at least about        20% (by wt) or at least about 30% (by wt) or at least about 50%        (by wt) of polyethylene oxide having, based on rheological        measurements, a molecular weight of at least 1,000,000.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, a molecular weight of at least 800,000 or at least        900,000; and    -   (2) at least one active agent selected from opioid analgesics;        and

wherein the composition comprises at least about 80% (by wt)polyethylene oxide.

In certain embodiments of the invention the extended release matrix hasa density which is equal to or less than about 1.20 g/cm³. In certainsuch embodiments, the density of the extended release matrix formulationis equal to or less than about 1.19 g/cm³, preferably equal to or lessthan about 1.18 g/cm³ or equal to or less than about 1.17 g/cm³. Forexample, the density of the extended release matrix formulation is inthe range of from about 1.10 g/cm³ to about 1.20 g/cm³, from about 1.11g/cm³ to about 1.20 g/cm³, or from about 1.11 g/cm³ to about 1.19 g/cm³.Preferably it is in the range of from about 1.12 g/cm³ to about 1.19g/cm³ or from about 1.13 g/cm³ to about 1.19 g/cm³, more preferably fromabout 1.13 g/cm³ to about 1.18 g/cm³.

Preferably, the density is determined by Archimedes principle, asdescribed above.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) at least one active agent; and

wherein the extended release matrix formulation when subjected to anindentation test has a cracking force of at least about 110 N.

In certain embodiments of the invention the extended release matrixformulation has a cracking force of at least about 110 N, preferably ofat least about 120 N, at least about 130 N or at least about 140 N, morepreferably of at least about 150 N, at least about 160 N or at leastabout 170 N, most preferably of at least about 180 N, at least about 190N or at least about 200 N.

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising at least:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight of at least        1,000,000; and    -   (2) at least one active agent; and

wherein the extended release matrix formulation when subjected to anindentation test has a “penetration depth to crack distance” of at leastabout 1.0 mm.

In certain embodiments of the invention the extended release matrixformulation has a “penetration depth to crack” distance of at leastabout 1.0 mm or at least about 1.2 mm, preferably of at least about 1.4mm, at least about 1.5 mm or at least about 1.6 mm, more preferably ofat least about 1.8 mm, at least about 1.9 mm or at least about 2.0 mm,most preferably of at least about 2.2 mm, at least about 2.4 mm or atleast about 2.6 mm.

In certain such embodiments of the invention the extended release matrixformulation has a cracking force of at least about 110 N, preferably ofat least about 120 N, at least about 130 N or at least about 140 N, morepreferably of at least about 150 N, at least about 160 N or at leastabout 170 N, most preferably of at least about 180 N, at least about 190N or at least about 200 N, and/or a “penetration depth to crack”distance of at least about 1.0 mm or at least about 1.2 mm, preferablyof at least about 1.4 mm, at least about 1.5 mm or at least about 1.6mm, more preferably of at least about 1.8 mm, at least about 1.9 mm orat least about 2.0 mm, most preferably of at least about 2.2 mm, atleast about 2.4 mm or at least about 2.6 mm. A combination of any of theaforementioned values of cracking force and “penetration depth to crack”distance is included in the scope of the present invention.

In certain such embodiments the extended release matrix formulation whensubjected to an indentation test resists a work of at least about 0.06 Jor at least about 0.08 J, preferably of at least about 0.09 J, at leastabout 0.11 J or at least about 0.13 J, more preferably of at least about0.15 J, at least about 0.17 J or at least about 0.19 J, most preferablyof at least about 0.21 J, at least about 0.23 J or at least about 0.25J, without cracking.

The parameters “cracking force”, “penetration depth to crack distance”and “work” are determined in an indentation test as described above,using a Texture Analyzer such as the TA-XT2 Texture Analyzer (TextureTechnologies Corp., 18 Fairview Road, Scarsdale, N.Y. 10583). Thecracking force and/or “penetration depth to crack” distance can bedetermined using an uncoated or a coated extended release matrixformulation. Preferably, the cracking force and/or “penetration depth tocrack” distance are determined on the uncoated extended release matrixformulation. Without wanting to be bound by any theory, it is believedthat a coating, such as the coating applied in step d) of themanufacturing process of the solid oral extended release pharmaceuticaldosage form as described above, does not significantly contribute to theobserved cracking force and/or “penetration depth to crack” distance.Therefore, the cracking force and/or “penetration depth to crack”distance determined for a specific coated extended release matrixformulation are not expected to vary substantially from the valuesdetermined for the corresponding uncoated extended release matrixformulation.

In certain embodiments the extended release matrix formulation is in theform of a tablet or multi particulates, and the tablet or the individualmulti particulates can at least be flattened without breaking,characterized by a thickness of the tablet or of the individual multiparticulate after the flattening which corresponds to no more than about60% of the thickness of the tablet or the individual multi particulatebefore flattening. Preferably, the tablet or the individual multiparticulates can at least be flattened without breaking, characterizedby a thickness of the tablet or the individual multi particulate afterthe flattening which corresponds to no more than about 50%, or no morethan about 40%, or no more than about 30%, or no more than about 20%, orno more than about 16% of the thickness of the tablet or the individualmulti particulate before flattening.

Preferably, the flattening of the tablets or the individual multiparticulates is performed with a bench press, such as a carver stylebench press, or with a hammer, as described above.

In certain such embodiments the extended release matrix formulation isin the form of a tablet or multi particulates, and the tablet or theindividual multi particulates can at least be flattened withoutbreaking, characterized by a thickness of the tablet or of theindividual multi particulate after the flattening which corresponds tono more than about 60% of the thickness of the tablet or the individualmulti particulate before flattening, and wherein said flattened tabletor the flattened multi particulates provide an in-vitro dissolutionrate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C., characterizedby the percent amount of active released at 0.5 hours or at 0.5 and 0.75hours, or at 0.5, 0.75 and 1 hours, or at 0.5, 0.75, 1 and 1.5 hours orat 0.5, 0.75, 1, 1.5 and 2 hours of dissolution that deviates no morethan about 20% points at each of said time points from the correspondingin-vitro dissolution rate of a non-flattened reference tablet orreference multi particulates. Preferably, the tablet or the individualmulti particulates can at least be flattened without breaking,characterized by a thickness of the tablet or the individual multiparticulate after the flattening which corresponds to no more than about50%, or no more than about 40%, or no more than about 30%, or no morethan about 20%, or no more than about 16% of the thickness of the tabletor the individual multi particulate before flattening, and wherein saidflattened tablet or the flattened multi particulates provide an in-vitrodissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpmin 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.,characterized by the percent amount of active released at 0.5 hours orat 0.5 and 0.75 hours, or at 0.5, 0.75 and 1 hours, or at 0.5, 0.75, 1and 1.5 hours or at 0.5, 0.75, 1, 1.5 and 2 hours of dissolution thatdeviates no more than about 20% points or no more than about 15% pointsat each of said time points from the corresponding in-vitro dissolutionrate of a non-flattened reference tablet or reference multiparticulates.

In certain embodiments the invention is directed to a solid oralextended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, wherein the extended release matrixformulation is in the form of a tablet or multi particulates, and thetablet or the individual multi particulates can at least be flattenedwithout breaking, characterized by a thickness of the tablet or of theindividual multi particulate after the flattening which corresponds tono more than about 60% of the thickness of the tablet or the individualmulti particulate before flattening, and wherein the flattened or nonflattened tablet or the flattened or non flattened multi particulatesprovide an in-vitro dissolution rate, when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) comprising 40% ethanol at 37° C., characterized by the percentamount of active released at 0.5 hours or at 0.5 and 0.75 hours, or at0.5, 0.75 and 1 hours, or at 0.5, 0.75, 1 and 1.5 hours or at 0.5, 0.75,1, 1.5 and 2 hours of dissolution that deviates no more than about 20%points at each time points from the corresponding in-vitro dissolutionrate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C. without ethanol,using a flattened and non flattened reference tablet or flattened andnon flattened reference multi particulates, respectively. Preferably,the tablet or the multi particulates can at least be flattened withoutbreaking, characterized by a thickness of the tablet or the individualmulti particulate after the flattening which corresponds to no more thanabout 60%, or no more than about 50%, or no more than about 40%, or nomore than about 30%, or no more than about 20%, or no more than about16% of the thickness of the tablet or the individual multi particulatebefore flattening, and wherein the flattened or non flattened tablet orthe individual multi particulates provide an in-vitro dissolution rate,when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) comprising 40% ethanol at37° C., characterized by the percent amount of active released at 0.5hours or at 0.5 and 0.75 hours, or at 0.5, 0.75 and 1 hours, or at 0.5,0.75, 1 and 1.5 hours or at 0.5, 0.75, 1, 1.5 and 2 hours of dissolutionthat deviates no more than about 20% points or no more than about 15%points at each of said time points from the corresponding in-vitrodissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in900 ml simulated gastric fluid without enzymes (SGF) at 37° C. withoutethanol, using a flattened and a non flattened reference tablet orreference multi particulates, respectively.

In certain such embodiments the extended release matrix formulation,when subjected to a maximum force of about 196 N or about 439 N in atablet hardness test, does not break.

Preferably, the tablet hardness test to determine the breaking strengthof extended release matrix formulations is performed in a SchleunigerApparatus as described above. For example, the breaking strength isdetermined using a Schleuniger 2E/106 Apparatus and applying a force ofa maximum of about 196 N, or a Schleuniger Model 6D Apparatus andapplying a force of a maximum of about 439 N.

It has also been observed that formulations of the present invention arestorage stable, wherein the extended release matrix formulation afterhaving been stored at 25° C. and 60% relative humidity (RH) or 40° C.and 75% relative humidity (RH) for at least 1 month, more preferably forat least 2 months, for at least 3 months or for at least 6 months,provides a dissolution rate, when measured in a USP Apparatus 1 (basket)at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at37° C., characterized by the percent amount of active released at 1hours or at 1 and 2 hours, or at 1 and 4 hours, or at 1, 2 and 4 hours,or at 1, 4 and 12 hours, or at 1, 2, 4 and 8 hours or at 1, 2, 4, 8 and12 hours of dissolution that deviates no more than about 15% points,preferably no more than about 12% points or no more than about 10%points, more preferably no more than about 8% points or no more thanabout 6% points, most preferably no more than about 5% points at each ofsaid time points from the corresponding in-vitro dissolution rate of areference formulation prior to storage. Preferably, the extended releasematrix formulation is stored in count bottles, such as 100 countbottles. Any combination of the aforementioned storage times,dissolution time points and deviation limits lies within the scope ofthe present invention.

According to a further storage stability aspect the extended releasematrix formulation after having been stored at 25° C. and 60% relativehumidity (RH) or at 40° C. and 75% relative humidity (RH) for at least 1month, more preferably for at least 2 months, for at least 3 months orfor at least 6 months, contains an amount of the at least one activeagent in % (by wt) relative to the label claim of the active agent forthe extended release matrix formulation that deviates no more than about10% points, preferably no more than about 8% points or no more thanabout 6% points, more preferably no more than about 5% points or no morethan about 4% points or no more than about 3% points from thecorresponding amount of active agent in % (by wt) relative to the labelclaim of the active agent for the extended release matrix formulation ofa reference formulation prior to storage. Preferably, the extendedrelease matrix formulation is stored in count bottles, such as 100 countbottles. Any combination of the aforementioned storage times anddeviation limits lies within the scope of the present invention.

According to certain such embodiments the active agent is oxycodonehydrochloride.

Preferably, the amount of the at least one active agent in % (by wt)relative to the label claim of the active agent for the extended releasematrix formulation is determined by extracting the at least one activeagent from the extended release matrix formulation and subsequentanalysis using high performance liquid chromatography. In certainembodiments, wherein the at least one active agent is oxycodonehydrochloride, preferably the amount of oxycodone hydrochloride in % (bywt) relative to the label claim of oxycodone hydrochloride for theextended release matrix formulation is determined by extracting theoxycodone hydrochloride from the extended release matrix formulationwith a 1:2 mixture of acetonitrile and simulated gastric fluid withoutenzyme (SGF) under constant magnetic stirring until the extended releasematrix formulation is completely dispersed or for overnight andsubsequent analysis using high performance liquid chromatography,preferably reversed-phase high performance liquid chromatography. Incertain such embodiments, wherein the extended release matrixformulation is in the form of tablets, preferably the amount ofoxycodone hydrochloride in % (by wt) relative to the label claim ofoxycodone hydrochloride for the tablets is determined by extractingoxycodone hydrochloride from two sets of ten tablets each with 900 mL ofa 1:2 mixture of acetonitrile and simulated gastric fluid without enzyme(SGF) under constant magnetic stirring until the tablets are completelydispersed or for overnight and subsequent analysis using highperformance liquid chromatography, preferably reversed-phase highperformance liquid chromatography. Preferably, the assay results aremean values on two measurements.

In certain embodiments the invention is directed to a solid oralextended release pharmaceutical dosage form wherein the dosage formprovides a dissolution rate, which when measured in a USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C., is between 12.5 and 55% (by wt) active agent releasedafter 1 hour, between 25 and 65% (by wt) active agent released after 2hours, between 45 and 85% (by wt) active agent released after 4 hoursand between 55 and 95% (by wt) active agent released after 6 hours, andoptionally between 75 and 100% (by wt) active agent released after 8hours. Preferably, the dosage form provides a dissolution rate, whichwhen measured in a USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C., between 15 and45% (by wt) active released after 1 hour, is between 30 and 60% (by wt)active agent released after 2 hours, between 50 and 80% (by wt) activeagent released after 4 hours and between 60 and 90% (by wt) active agentreleased after 6 hours and optionally between 80 and 100% (by wt) activeagent released after 8 hours. More preferably, the dosage form providesa dissolution rate, which when measured in a USP Apparatus 1 (basket) at100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°C., is between 17.5 and 35% (by wt) active agent released after 1 hour,between 35 and 55% (by wt) active agent released after 2 hours, between55 and 75% (by wt) active agent released after 4 hours and between 65and 85% (by wt) active agent released after 6 hours and optionallybetween 85 and 100% (by wt) active agent released after 8 hours.

In certain such embodiments the active agent is oxycodone hydrochlorideor hydromorphone hydrochloride.

Such dosage forms may be prepared by the process as described herein.

In embodiments as described above the tablet may be formed by directcompression of the composition and cured by at least subjecting saidtablet to a temperature of at least about 60° C., at least about 62° C.,at least about 68° C., at least about 70° C., at least about 72° C. orat least about 75° C. for a time period of at least about 1 minute, atleast about 5 minutes or at least about 15 minutes.

In certain embodiments of the invention the tablet as described abovemay be over coated with a polyethylene oxide powder layer by applying tothe cured or uncured tablet a powder layer of polyethylene oxidesurrounding the core and cure the powder layered tablet as describedabove. Such an outer polyethylene oxide layer provides a lag time beforethe release of the active agent starts and/or a slower overall releaserate.

In certain embodiments of the invention a stacked bi or multi layeredtablet is manufactured, wherein at least one of the layers contains anextended release formulation as described above and at least one of theother layers contains an immediate release formulation of the activeagent contained by the extended release formulation or a seconddifferent active agent. In certain such embodiments the tablet is a bilayered tablet with on extended release formulation layer as describedherein and an immediate release formulation layer. In certain suchembodiments, in particular the bi layered tablets, opioid analgesics arecontained by the extended release layer and further non opioidanalgesics are contained by the immediate release layer. Non opioidanalgesics may be non steroidal anti inflammatory agents but also nonopioid analgesics such as acetaminophen. Acetaminophen can e.g. be usedin combination with hydrocodone as opioid analgesic. Such tablets can beprepared by specific tablet compression techniques which allow thecompression of at least two compositions to form tablets with at leasttwo distinct stacked layers each comprising one of the at least twocompositions. For example, such tablets can be manufactured in a tabletpress by filling the compression tool with the first composition andcompressing said first composition and subsequently filling on top ofthe compressed first composition the second composition and subsequentlycompressing the two compositions to form the final layered tablet. Theimmediate release composition may be any composition as known in theart.

The invention also encompasses the use of high molecular weightpolyethylene oxide that has, based on rheological measurements, anapproximate molecular weight of at least 1,000,000, as matrix formingmaterial in the manufacture of a solid extended release oral dosage formcomprising an active selected from opioids for imparting to the solidextended release oral dosage form resistance to alcohol extraction. Theuse may be accomplished as described herein with respect to thedescribed process or the described formulations or in any other way asconventional in the art.

It has been observed that the formulations of the present inventioncomprising a high molecular weight polyethylene oxide can be flattenedto a thickness of between about 15 and about 18% of the non flattenedthickness and that the flat tablet resumes in part or substantiallyresumes its initial non flattened shape during dissolution, neglectingthe swelling that also takes place during dissolution, i.e. thethickness of the tablet increases and the diameter decreasesconsiderably during dissolution. Without wanting to be bound to anytheory it is believed that the high molecular weight polyethylene oxidehas a form memory and the ability to restore the initial form afterdeformation, e.g. after flattening, in an environment that allows therestoration, such as an aqueous environment used in dissolution tests.This ability is believed to contribute to the tamper resistance, inparticular the alcohol resistance of the dosage forms of the presentinvention.

The invention also encompasses the method of treatment wherein a dosageform is administered for treatment of a disease or certain condition ofa patient that requires treatment in particular pain and the use of adosage form according to the invention for the manufacture of amedicament for the treatment of a disease or certain condition of apatient that requires treatment in particular pain.

In one aspect of the present invention, a twice-a-day solid oralextended release pharmaceutical dosage form is provided which provides amean t_(max) at about 2 to about 6 hours or at about 2.5 to about 5.5hours or at about 2.5 to about 5 hours after administration at steadystate or of a single dose to human subjects. The dosage form maycomprises oxycodone or a salt thereof or hydromorphone or a saltthereof.

In one aspect of the present invention, a once-a-day solid oral extendedrelease pharmaceutical dosage form is provided which provides a meant_(max) at about 3 to about 10 hours or at about 4 to about 9 hours orat about 5 to about 8 hours after administration at steady state or of asingle dose to human subjects. The dosage form may comprises oxycodoneor a salt thereof or hydromorphone or a salt thereof.

In a further aspect of the present invention, a twice-a-day solid oralextended release pharmaceutical dosage form is provided, wherein thedosage form comprises oxycodone or a salt thereof in an amount of fromabout 10 mg to about 160 ing and wherein the dosage form provides a meanmaximum plasma concentration (C_(max)) of oxycodone up to about 240ng/mL or from about 6 ng/mL to about 240 ng/mL after administration atsteady state or of a single dose to human subjects.

In a further aspect of the present invention, a solid oral extendedrelease pharmaceutical dosage form is provided, wherein the dosage formcomprises oxycodone or a salt thereof in an amount of from about 10 mgto about 40 mg and wherein the dosage form provides a mean maximumplasma concentration (C_(max)) of oxycodone from about 6 ng/mL to about60 ng/mL after administration at steady state or of a single dose tohuman subjects.

In a further aspect of the invention a solid oral extended releasepharmaceutical dosage form is provided that is bioequivalent to thecommercial product OxyContin™.

In a further aspect of the invention a solid oral extended releasepharmaceutical dosage form is provided that is bioequivalent to thecommercial product Palladone™ as sold in the United States in 2005.

In a further aspect of the invention, a solid oral extended releasepharmaceutical dosage form is provided, wherein the active agent isoxycodone hydrochloride and

wherein a dosage form comprising 10 mg of oxycodone hydrochloride whentested in a comparative clinical study is bioequivalent to a referencetablet containing 10 mg of oxycodone hydrochloride in a matrixformulation containing:

a) Oxycodone hydrochloride: 10.0 mg/tablet

b) Lactose (spray-dried): 69.25 mg/tablet

c) Povidone: 5.0 mg/tablet

d) Eudragit® RS 30D (solids): 10.0 mg/tablet

e) Triacetin®: 2.0 mg/tablet

f) Stearyl alcohol: 25.0 mg/tablet

g) Talc: 2.5 mg/tablet

h) Magnesium Stearate: 1.25 mg/tablet;

and wherein the reference tablet is prepared by the following steps:

-   1. Eudragit® RS 30D and Triacetin® are combined while passing    through a 60 mesh screen, and mixed under low shear for    approximately 5 minutes or until a uniform dispersion is observed.-   2. Oxycodone HCl, lactose, and povidone are placed into a fluid bed    granulator/dryer (FBD) bowl, and the suspension sprayed onto the    powder in the fluid bed.-   3. After spraying, the granulation is passed through a #12 screen if    necessary to reduce lumps.-   4. The dry granulation is placed in a mixer.-   5. In the meantime, the required amount of stearyl alcohol is melted    at a temperature of approximately 70° C.-   6. The melted stearyl alcohol is incorporated into the granulation    while mixing.-   7. The waxed granulation is transferred to a fluid bed    granulator/dryer or trays and allowed to cool to room temperature or    below.-   8. The cooled granulation is then passed through a #12 screen.-   9. The waxed granulation is placed in a mixer/blender and lubricated    with the required amounts of talc and magnesium stearate for    approximately 3 minutes.-   10. The granulate is compressed into 125 mg tablets on a suitable    tabletting machine.

Pharmacokinetic parameters such as C_(max) and t_(max), AUC_(t),AUC_(inf), etc. describing the blood plasma curve can be obtained inclinical trials, first by single-dose administration of the activeagent, e.g. oxycodone to a number of test persons, such as healthy humansubjects. The blood plasma values of the individual test persons arethen averaged, e.g. a mean AUC, C_(max) and t_(max) value is obtained.In the context of the present invention, pharmacokinetic parameters suchas AUC, C_(max) and t_(max) refer to mean values. Further, in thecontext of the present invention, in vivo parameters such as values forAUC, C_(max), t_(max), or analgesic efficacy refer to parameters orvalues obtained after administration at steady state or of a single doseto human patients.

The C_(max) value indicates the maximum blood plasma concentration ofthe active agent. The t_(max) value indicates the time point at whichthe C_(max) value is reached. In other words, t_(max) is the time pointof the maximum observed plasma concentration.

The AUC (Area Under the Curve) value corresponds to the area of theconcentration curve. The AUC value is proportional to the amount ofactive agent absorbed into the blood circulation in total and is hence ameasure for the bioavailability.

The AUC_(t) value corresponds to the area under the plasmaconcentration-time curve from the time of administration to the lastmeasurable plasma concentration and is calculated by the linear up/logdown trapezoidal rule.

AUC_(inf) is the area under the plasma concentration-time curveextrapolated to infinity and is calculated using the formula:

${AUC}_{\inf} = {{AUC}_{t} + \frac{C_{t}}{\lambda_{z}}}$

where C_(t) is the last measurable plasma concentration and λ_(Z) is theapparent terminal phase rate constant.

λ_(Z) is the apparent terminal phase rate constant, where λ_(Z) is themagnitude of the slope of the linear regression of the log concentrationversus time profile during the terminal phase.

t_(1/2Z) is the apparent plasma terminal phase half-life and is commonlydetermined as t_(1/2Z)=(ln 2)/λ_(Z).

The lag time t_(lag) is estimated as the timepoint immediately prior tothe first measurable plasma concentration value.

The term “healthy” human subject refers to a male or female with averagevalues as regards height, weight and physiological parameters, such asblood pressure, etc. Healthy human subjects for the purposes of thepresent invention are selected according to inclusion and exclusioncriteria which are based on and in accordance with recommendations ofthe International Conference for Harmonization of Clinical Trials (ICH).

Thus, inclusion criteria comprise males and females aged between 18 to50 years, inclusive, a body weight ranging from 50 to 100 kg (110 to 220lbs) and a Body Mass Index (BMI) ≧18 and ≦34 (kg/m²), that subjects arehealthy and free of significant abnormal findings as determined bymedical history, physical examination, vital signs, andelectrocardiogram, that females of child-bearing potential must be usingan adequate and reliable method of contraception, such as a barrier withadditional spermicide foam or jelly, an intra-uterine device, hormonalcontraception (hormonal contraceptives alone are not acceptable), thatfemales who are postmenopausal must have been postmenopausal ≧1 year andhave elevated serum follicle stimulating hormone (FSH), and thatsubjects are willing to eat all the food supplied during the study.

A further inclusion criterium may be that subjects will refrain fromstrenuous exercise during the entire study and that they will not begina new exercise program nor participate in any unusually strenuousphysical exertion.

Exclusion criteria comprise that females are pregnant (positive betahuman chorionic gonadotropin test) or lactating, any history of orcurrent drug or alcohol abuse for five years, a history of or anycurrent conditions that might interfere with drug absorption,distribution, metabolism or excretion, use of an opioid-containingmedication in the past thirty (30) days, a history of known sensitivityto oxycodone, naltrexone, or related compounds, any history of frequentnausea or emesis regardless of etiology, any history of seizures or headtrauma with current sequelae, participation in a clinical drug studyduring the thirty (30) days preceding the initial dose in this study,any significant illness during the thirty (30) days preceding theinitial dose in this study, use of any medication including thyroidhormone replacement therapy (hormonal contraception is allowed),vitamins, herbal, and/or mineral supplements, during the 7 dayspreceding the initial dose, refusal to abstain from food for 10 hourspreceding and 4 hours following administration or for 4 hours followingadministration of the study drugs and to abstain from caffeine orxanthine entirely during each confinement, consumption of alcoholicbeverages within forty-eight (48) hours of initial study drugadministration (Day 1) or anytime following initial study drugadministration, history of smoking or use of nicotine products within 45days of study drug administration or a positive urine cotinine test,blood or blood products donated within 30 days prior to administrationof the study drugs or anytime during the study, except as required bythe clinical study protocol, positive results for urine drug screen,alcohol screen at check-in of each period, and hepatitis B surfaceantigen (HBsAg), hepatitis B surface antibody HBsAb (unless immunized),hepatitis C antibody (anti-HCV), a positive Naloxone HCl challenge test,presence of Gilbert's Syndrome or any known hepatobiliary abnormalitiesand that the Investigator believes the subject to be unsuitable forreason(s) not specifically stated above.

Subjects meeting all the inclusion criteria and none of the exclusioncriteria will be randomized into the study.

The enrolled population is the group of subjects who provide informedconsent.

The randomized safety population is the group of subjects who arerandomized, receive study drug, and have at least one post dose safetyassessment.

The full analysis population for PK metrics will be the group ofsubjects who are randomized, receive study drug, and have at least onevalid PK metric. Subjects experiencing emesis within 12 hours afterdosing might be included based on visual inspection of the PK profilesprior to database lock. Subjects and profiles/metrics excluded from theanalysis set will be documented in the Statistical Analysis Plan.

For the Naloxone HCl challenge test, vital signs and pulse oximetry(SPO₂) are obtained prior to the Naloxone HCl challenge test. TheNaloxone HCl challenge may be administered intravenously orsubcutaneously. For the intravenous route, the needle or cannula shouldremain in the arm during administration. 0.2 mg of Naloxone HCl (0.5 mL)are administered by intravenous injection. The subject is observed for30 seconds for evidence of withdrawal signs or symptoms. Then 0.6 mg ofNaloxone HCl (1.5 mL) are administered by intravenous injection. Thesubject is observed for 20 minutes for signs and symptoms of withdrawal.For the subcutaneous route, 0.8 mg of Naloxone HCl (2.0 mL) areadministered and the subject is observed for 20 minutes for signs andsymptoms of withdrawal. Following the 20-minute observation,post-Naloxone HCl challenge test vital signs and SPO₂ are obtained.

Vital signs include systolic blood pressure, diastolic blood pressure,pulse rate, respiratory rate, and oral temperature.

For the “How Do You Feel?” Inquiry, subjects will be asked a non-leading“How Do You Feel?” question such as “Have there been any changes in yourhealth status since screening/since you were last asked?” at each vitalsign measurement. Subject's response will be assessed to determinewhether an adverse event is to be reported. Subjects will also beencouraged to voluntarily report adverse events occurring at any othertime during the study.

Each subject receiving a fed treatment will consume a standard high-fatcontent meal in accordance with the “Guidance for Industry: Food-EffectBioavailability and Fed Bioequivalence Studies” (US Department of Healthand Human Services, Food and Drug Administration, Center for DrugEvaluation and Research, December 2002). The meal will be provided 30minutes before dosing and will be eaten at a steady rate over a25-minute period so that it is completed by 5 minutes before dosing.

Clinical laboratory evaluations performed in the course of clinicalstudies include biochemistry (fasted at least 10 hours), hematology,serology, urinalysis, screen for drugs of abuse, and further tests.

Biochemistry evaluations (fasted at least 10 hours) includedetermination of albumin, Alkaline Phosphatase, alanine aminotransferase(alanine transaminase, ALT), aspartate aminotransferase (aspartatetransaminase, AST), calcium, chloride, creatinine, glucose, inorganicphosphate, potassium, sodium, total bilirubin, total protein, urea,lactate dehydrogenase (LDH), direct bilirubin and CO₂.

Hematology evaluations include determination of hematocrit, hemoglobin,platelet count, red blood cell count, white blood cell count, whiteblood cell differential (% and absolute): basophils, eosinophils,lymphocytes, monocytes and neutrophils.

Serology evaluations include determination of hepatitis B surfaceantigen (HBsAg), hepatitis B surface antibody (HBsAb) and hepatitis Cantibody (anti-HCV).

Urinalysis evaluations include determination of color, appearance, pH,glucose, ketones, urobilinogen, nitrite, occult blood, protein,leukocyte esterase, microscopic and macroscopic evaluation, specificgravity.

Screen for drugs of abuse includes urine screen with respect to opiates,amphetamines, cannabinoids, benzodiazepines, cocaine, cotinine,barbiturates, phencyclidine, methadone and propoxyphene and alcoholtests, such as blood alcohol and breathalyzer test.

Further tests for females only include serum pregnancy test, urinepregnancy test and serum follicle stimulating hormone (FSH) test (forself reported postmenopausal females only).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction of the invention.

Example 1

In Example 1 a 200 mg tablet including 10 mg of oxycodone HCl wasprepared using high molecular weight polyethylene oxide in combinationwith hydroxypropyl cellulose.

Composition:

Ingredient mg/unit % Oxycodone HCl 10 5 Polyethylene Oxide (MW:approximately 4,000,000; 160 80 Polyox ™ WSR-301) HydroxypropylCellulose 30 15 (Klucel ™ HXF) Total 200 100

Process of Manufacture:

The processing steps to manufacture tablets were as follows:

-   1. Oxycodone HCl, Polyethylene Oxide and hydroxypropyl cellulose was    dry mixed in a low/high shear Black & Decker Handy Chopper dual    blade mixer with a 1.5 cup capacity.-   2. Step 1 blend was compressed to target weight on a single station    tablet Manesty Type F 3 press-   3. Step 2 tablets were spread onto a tray and placed in a Hotpack    model 435304 oven at 70° C. for approximately 14.5 hours to cure the    tablets.

In vitro testing including testing tamper resistance (hammer andbreaking strength test) and resistance to alcohol extraction wasperformed as follows.

The tablets were tested in vitro using USP Apparatus 2 (paddle) at 50rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.,using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at 230 nM. Theresults are presented in Table 1.1.

Uncured tablets, cured tablets and tampered, i.e. flattened, curedtablets were tested. The cured tablets were flattened with a hammerusing 7 manually conducted hammer strikes to impart physical tampering.The tablet dimensions before and after the flattening and thedissolution profiles were evaluated on separate samples. The results arepresented in Table 1.1.

As a further tamper resistance test, the cured tablets were subjected toa breaking strength test applying a force of a maximum of 196 Newtonusing a Schleuniger 2E/106 Apparatus to evaluate the resistance tobreaking. The results are also presented in Table 1.1.

In addition, cured tablets were tested in vitro using ethanol/SGF mediaat ethanol concentrations of 0%, 20% and 40% to evaluate alcoholextractability. Testing was performed using USP Apparatus 2 (paddle) at50 rpm in 500 ml of media at 37° C., using a Perkin Elmer UV/VISSpectrometer Lambda 20, UV at 220 nM. Sample time points include 0.5 and1 hour. The results are also presented in Table 1.2.

TABLE 1.1 Cured Uncured Flattened by 7 whole Whole hammer strikes TabletThickness (mm)     4.52 ¹      4.39 ¹     2.23 ² Dimen- Diameter (mm) —     7.56 ¹     10.27 ² sions Breaking —     196+ ³ — strength (N)Diameter (mm) —      7.33 ¹ — post breaking strength test Dissolution0.5 hr 13   34 33  (%   1 hr 18   46 45  Released)   2 hr 28   63 62  (n= 3 tabs   4 hr 43   81 83  per   8 hr 65   86 87  vessel)  17 hr 85  86 87  ¹ n = median of 3 measurements ² n = median of 5 measurements ³196+ means that subjected to the maximum force of 196 Newton the tabletsdid not break, n = median of 3 measurements

TABLE 1.2 Dissolution (% Released) (n = 2 tabs per vessel) 0% Ethanol20% Ethanol 40% Ethanol Concentration in Concentration in Concentrationin SGF SGF SGF Time uncured cured uncured cured uncured cured 0.5 13 3713 32 11 33 1 22 50 21 46 22 43

Example 2

In Example 2 three different 100 mg tablets including 10 and 20 mg ofOxycodone HCl were prepared using high molecular weight polyethyleneoxide and optionally hydroxypropyl cellulose.

Compositions:

Example 2.1 Example 2.2 Example 2.3 Ingredient mg/unit mg/unit mg/unitOxycodone HCl 10 20 10 Polyethylene Oxide (MW: approximately 4,000,000;90 80 85 Polyox ™ WSR301) Hydroxypropyl Cellulose 0 0 5 (Klucel ™ IIXF)Total 100 100 100

Process of Manufacture:

The processing steps to manufacture tablets were as follows:

-   1. Oxycodone HCl, Polyethylene Oxide and Hydroxypropyl Cellulose    were dry mixed in a low/high shear Black & Decker Handy Chopper dual    blade mixer with a 1.5 cup capacity.-   2. Step 1 blend was compressed to target weight on a single station    tablet Manesty Type F 3 press.-   3. Step 2 tablets were spread onto a tray placed in a Hotpack model    435304 oven at 70-75° C. for approximately 6 to 9 hours to cure the    tablets.

In vitro testing including testing for tamper resistance (bench pressand breaking strength test) was performed as follows.

The cured tablets were tested in vitro using USP Apparatus 2 (paddle) at50 rpm in 500 ml simulated gastric fluid without enzymes (SGF) at 37°C., using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at 220 nM.Cured tablets and cured flattened tablets were tested. The tablets wereflattened using 2500 psi with a Carver style bench press to impartphysical tampering. The results are presented in Table 2.

As a further tamper resistance test, the cured tablets were subjected toa breaking strength test applying a force of a maximum of 196 Newtonusing a Schleuniger 2E/106 Apparatus to evaluate the resistance tobreaking. The results are presented in Table 2.

TABLE 2 Example 2.1 Example 2.2 Example 2.3 Flattened FlattenedFlattened by by by Whole bench Whole bench Whole bench (n = 6) press (n= 2) press (n = 5) press Tablet Thickness    3.36 0.58    3.14 0.84   3.48 0.49 Dimensions (mm) Diameter    6.48 12.80    6.58 13.44   6.46 12.86 (mm) Thickness — 17.3 — 26.8 — 14.0 (%) Breaking  196+¹n/a  196+¹ n/a  196+¹ n/a strength (N) Dissolution 0.5 hr 34 46 42 50 4056 (%   1 hr 50 62 57 71 55 72 Released)   2 hr 72 78 78 91 77 89 (n= 1)   4 hr 81 82 95 93 93 100   8 hr 82 82 95 93 94 100  12 hr 83 82 9694 95 101 ¹196+ means that subjected to the maximum force of 196 Newtonthe tablets did not break

Example 3

In Example 3 a 200 mg tablet prepared including 10 mg oxycodone HCl andhigh molecular weight polyethylene oxide were prepared.

Composition:

Ingredient mg/unit % Oxycodone HCl 10 5 Polyethylene Oxide 188 94 (MW:approximately 4,000,000; Polyox ™ WSR301) Magnesium Stearate 2 1 Total200 100

Process of Manufacture:

The processing steps to manufacture tablets were as follows:

-   1. Oxycodone HCl, Polyethylene Oxide and Magnesium Stearate were dry    mixed in a low/high shear Black & Decker Handy Chopper dual blade    mixer with a 1.5 cup capacity.-   2. Step 1 blend was compressed to target weight on a single station    tablet Manesty Type F 3 press.-   3. Step 2 tablets were placed onto a tray placed in a Hotpack model    435304 oven at 70° C. for 1 to 14 hours to cure the tablets.

In vitro testing including testing for tamper resistance (breakingstrength test) was performed as follows:

The tablets were tested in vitro using USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.,using a Perkin Elmer UV/VIS Spectrometer Lambda 20 USP Apparatus, UV at220 nM, after having been subjected to curing for 2, 3, 4, 8, and 14hours. Tablet dimensions of the uncured and cured tablets anddissolution results are presented in Table 3.

As a further tamper resistance test, the cured and uncured tablets weresubjected to a breaking strength test applying a force of a maximum of196 Newton using a Schleuniger 2E/106 Apparatus to evaluate theresistance to breaking. The results are presented in Table 3.

TABLE 3 Un- Cure Time (hours) Cured² 1¹ 2¹ 4¹ 8¹ 14² Tablet Weight 208208    209  209  208  210  Dimensions (mg) Thickness 4.74 5.17    5.25   5.17    5.17    4.85 (mm) Diameter 7.93 7.85    7.80    7.75    7.69   7.64 (mm) Breaking 176 196+³     196+³  196+³  196+³  196+³ strength(N) Dissolution 0.5 hr Not Not 16 11 15 33 (%   1 hr tested tested 23 1823 50 Released)   2 hr 34 28 36 69 (n = 2)   4 hr 54 45 58 87   8 hr 8169 83 93  12 hr 96 83 92 94 ¹Tablet dimensions n = 4 ²Tablet dimensionsn = 10 ³196+ means that subjected to the maximum force of 196 Newton thetablets did not break.

Example 4

In Example 4 six different 100 mg tablets (Examples 4.1 to 4.6)including 10 mg of oxycodone HCl are prepared varying the amount andmolecular weight of the used polyethylene oxides.

Compositions:

4.1 4.2 4.3 4.4 4.5 4.6 mg/ mg/ mg/ mg/ mg/ mg/ Ingredient unit unitunit unit unit unit Oxycodone HCl 10 10 10 10 10 10 Polyethylene Oxide89.5 79.5 69.5 89.0 0 0 (MW: approximately 4,000,000; Polyox ™ WSR 301)Polyethylene Oxide 0 10 20 0 0 0 (MW; approximately 100,000; Polyox ™N10) Polyethylene Oxide 0 0 0 0 0 89.5 (MW: approximately 2,000,000;Polyox ™N-60K) Polyethylene Oxide 0 0 0 0 89.5 0 MW; approximately7,000,000; Polyox ™ WSR 303) Butylated 0 0 0 0.5 0 0 Hydroxytoluene(BHT) Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 0.5 Total 100 100 100 100100 100 Blend size (g) 125 125 125 125 157.5 155.5 Total Batch size (g)250 250 250 250 157.5 155.5 (amount manufactured)The processing steps to manufacture tablets were as follows:

-   1. Oxycodone HCl and Polyethylene Oxide (and BHT if required) were    dry mixed for 30 seconds in a low/high shear Black & Decker Handy    Chopper dual blade mixer-   2. Magnesium stearate was added to Step 1 blend and mixed for an    additional 30 seconds.-   3. Step 2 blend was compressed to target weight on a single station    tablet Manesty Type F 3 press using standard round (0.2656 inch)    concave tooling-   4. Step 3 tablets were loaded into a 15 inch coating pan (LCDS    Vector Laboratory Development Coating System) at 38 rpm equipped    with one baffle. A temperature probe (wire thermocouple) was placed    inside the coating pan near the bed of tablets to monitor the bed    temperature. The tablet bed was heated to a temperature of about 70    about 80° C. (the temperature can be derived from Tables 4.1 to 4.6    for each Example) for a minimum of 30 minutes and a maximum of 2    hours. The tablet bed was then cooled and discharged.

In vitro testing including testing for tamper resistance (breakingstrength and hammer test) was performed as follows:

Uncured and tablets cured at 0.5, 1, 1.5 and 2 hours of curing weretested in vitro using USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C., using a PerkinElmer UV/VIS Spectrometer Lambda 20, UV wavelength at 220 nM. Tabletdimensions and dissolution results corresponding to the respectivecuring time and temperature are presented in Tables 4.1 to 4.6.

As a further tamper resistance test, the cured and uncured tablets weresubjected to a breaking strength test applying a force of a maximum of196 Newton using a Schleuniger 2E/106 Apparatus to evaluate theresistance to breaking. The results are provided in Tables 4.1 to 4.6.

Additionally, the tablets were flattened with a hammer using 10 manuallyconducted hammer strikes to impart physical tampering (hammer test).

TABLE 4.1 Example 4.1 Uncured Cure Time (hours) (n = 5) (n = 10) 0.5 1.01.5 2.0 Tablet Weight (mg) 108 109  108  107  107  Dimensions Thickness(mm) 3.64    3.93    3.94    3.90    3.83 Diameter (mm) 6.74    6.62   6.57    6.55    6.52 Breaking strength 94  196+²  196+²  196+²  196+²(N) Diameter (mm) mashed¹    5.15    5.38    5.23    5.44 post breakingstrength test (measured directly after the test) Curing 0 min   19.7 — —— Process 10 min —   66.2 — — — Tablet Bed 20 min —   68.6 — — — Temp °C. 30 min —   73.5 — — — (temperature 40 min — —   76.9 — — probe 60 min— —   78.9 — — within the 90 min — — —   79.8 — pan) 120 min — — — —  80.2 n = 3 3 2 2 2 Dissolution 0.5 hr 19 21 18 18 19 (% 1 hr 30 32 3029 31 Released) 2 hr 47 49 46 46 50 4 hr 71 76 70 69 75 8 hr 93 96 91 8993 12 hr 99 99 96 93 96 n = 1 1 1 Post Hammer Test³ (10 strikes n/a   1.70    2.18    2.37    2.09 applied manually)    2.31    2.06   2.26 Thickness (mm)    2.39    2.66    2.28 ¹Tablets mashed andcrumbled during the breaking strength test ²196+ means that subjected tothe maximum force of 196 Newton the tablets did not break ³Applied 10hammer strikes, the tablets flattened but did not break apart, hammeringimparted some edge splits.

TABLE 4.2 Example 4.2 Uncured Cure Time (hours) (n = 5) (n = 10) 0.5 1.01.5 2.0 Tablet Weight (mg) 108 109    109    109    107    DimensionsThickness (mm) 3.65 3.90 3.92 3.87 3.74 Diameter (mm) 6.74 6.61 6.546.52 6.46 Breaking strength (N) 93 196+³    196+³    196+³    196+³   Diameter (mm) mashed² 5.40 5.37 5.36 5.61 post breaking strength test(measured directly after the test) Relaxed diameter (mm) — 5.60 5.525.48 5.73 post breaking strength test (NLT 15 min relax period) Curing 0min 20.2  — — — Process 10 min — 71.6  — — — Tablet Bed 20 min — 74.9  —— — Temp ° C. 30 min — 76.1  — — — (temperature 40 min — — 79.8  — —probe within 60 min — — 80.2  — — the pan) 90 min — — — 76.4  — 120 min— — — — 77.5  Dissolution 0.5 hr — 20    20    — 29    (% Released) 1 hr— 30    31    — 44    (n = 3) 2 hr — 47    47    — 66    4 hr — 70   70    — 90    8 hr — 89    91    — 95    12 hr — 92    94    — 94    n =1 1 1 1 Post Hammer Test (10 strikes n/a 1.98 2.00 1.80 1.62 appliedmanually) 1.96 1.76 2.06 1.95 Thickness (mm) 1.99 1.79 1.98 1.53²Tablets mashed and crumbled during the breaking strength test ³196+means that subjected to the maximum force of 196 Newton the tablets didnot break.

TABLE 4.3 Example 4.3 Uncured (n = Cure Time (hours) (n = 5) 10) 0.5 1.01.5 2.0 Tablet Weight (mg) 108 107    108    108    107    DimensionsThickness (mm) 3.63 3.85 3.82 3.78 3.72 Diameter (mm) 6.74 6.61 6.556.48 6.46 Breaking strength (N) 91 196+³   196+³   196+³   196+³  Diameter (mm) mashed² 5.58 5.60 5.56 5.72 post breaking strength test(measured directly after the test) Relaxed diameter (mm) — 5.77 5.755.68 5.82 post breaking strength test (NLT 15 min relax period) Curing 0min 20.3  — — — Process 10 min — 71.0  — — — Tablet Bed 20 min — 74.1  —— — Temp ° C. 30 min — 75.9  — — — (temperature 40 min — — 76.5  — —probe within 60 min — — 77.8  — — the pan 90 min — — — 76.0  — withinthe 120 min — — — — 80.2  pan) n = 3 3 2 Dissolution 0.5 hr — 22   23    — 33    (% Released) 1 hr — 32    35    — 52    2 hr — 49    54   — 76    4 hr — 70    80    — 93    8 hr — 94    95    — 96    12 hr —96    96    — 96    n = 1 1 1 1 Post Hammer Test (10 strikes n/a 2.161.95 1.43 1.53 applied manually) 1.96 1.85 1.67 1.66 Thickness (mm) 1.912.03 1.65 2.08 ²Tablets mashed and crumbled during the breaking strengthtest ³196+ means that subjected to the maximum force of 196 Newton thetablets did not break.

TABLE 4.4 Example 4.4 Uncured (n = Cure Time (hours) (n = 5) 10) 0.5 1.01.5 2.0 Tablet Weight (mg) 101 101    101    101    101    DimensionsThickness (mm) 3.49 3.75 3.71 3.69 3.70 Diameter (mm) 6.75 6.59 6.556.55 6.52 Breaking strength (N) 81 196+³   196+³   196+³   196+³  Diameter (mm) mashed² 5.39 5.39 5.39 5.47 post breaking strength test(measured directly after the test Relaxed diameter (mm) — 5.58 5.59 5.585.63 post breaking strength test (NLT 15 min relax period) Curing 0 min37.3  Process 5 min — 67.0  — — — Tablet Bed 10 min — 71.8  — — — Temp °C. 20 min — 74.6  — — — (temperature 30 min — 76.2  — — — probe within40 min — — 77.0  — — the pan) 60 min — — 78.7  — — 90 min — — — 80.3  —120 min — — — — 79.3  Dissolution 0.5 hr — 17    16    — — (% Released)1 hr — 26    25    — — (n = 3) 2 hr — 41    40    — — 4 hr — 63    59   — — 8 hr — 79    75    — — 12 hr — 82    80    — — n = 1 1 1 1 PostHammer Test (10 strikes — 2.11 2.42 2.14 2.18 applied manually) 2.292.25 2.28 2.09 Thickness (mm) 2.32 2.13 2.07 2.36 ²Tablets mashed andcrumbled during the breaking strength test. ³196+ means that subjectedto the maximum force of 196 Newton the tablets did not break.

TABLE 4.5 Example 4.5 Uncured (n = Cure Time (hours) (n = 5) 10) 0.5 1.01.5 2.0 Tablet Weight (mg) 108 108    107    107    107    DimensionsThickness (mm) 3.61 3.87 3.84 3.84 3.84 Diameter (mm) 6.74 6.69 6.636.61 6.59 Breaking strength (N) 116 196+³   196+³   196+³   196+³  Diameter (mm) mashed² 5.49 5.59 5.51 5.54 post breaking strengthtest(measured directly after the test Diameter (mm) post — 5.67 5.765.67 5.68 breaking strength test (NLT 15 min relax period) Curing 0 min19.8  Process 5 min — 56.8  — — — Tablet Bed 10 min — 70.0  — — — Temp °C. 20 min — 74.6  — — — (temperature 30 min — 76.2  — — — probe within40 min — — 77.0  — — the pan) 60 min — — 78.2  — — 90 min — — — 80.2  —120 min — — — — 80.3  Dissolution 0.5 hr — 21    20    — — (% Released)1 hr — 33    32    — — (n = 3) 2 hr — 51    51    — — 4 hr — 75    76   — — 8 hr — 96    96    — — 12 hr — 100    100    — — n = 1 1 1 1 PostHammer Test (10 strikes — 2.19 2.31 2.36 2.45 applied manually) 2.152.48 2.42 2.08 Thickness (mm) 2.10 2.28 2.19 2.28 ²Tablets mashed andcrumbled during the breaking strength test ³196+ means that subjected tothe maximum force of 196 Newton the tablets did not break.

TABLE 4.6 Example 4.6 UnCured Cure Time (n = 5) (n = 6) 10 min 20 min0.5 hr 1.0 hr 1.5 hr 2.0 hr Tablet Weight (mg) 110 108 108 109 108 109109 Dimensions Thickness 3.65 3.93 3.89 3.89 3.87 3.85 3.85 (mm)Diameter 6.73 6.71 6.63 6.61 6.57 6.55 6.53 (mm) Breaking 128 196+²strength (N) Diameter mashed¹ 5.27 5.47 5.51 5.51 5.56 5.63 (mm) postbreaking strength test (measured directly after the test Diameter — 5.485.60 5.67 5.66 5.69 5.76 (mm) post breaking strength test (NLT 15 minrelax period) Curing 0 min 30.8 Process 5 min — 70.5 — — — — — TabletBed 10 min — 79.5 — — — — — Temp ° C. 20 min — — 79.9 — — — —(temperature 30 min — — — 79.6 — — — probe within 40 min — — — — 80.0 —— the pan) 60 min — — — — 79.8 — — 90 min — — — — — 80.2 — 120 min — — —— — — 80.4 Dissolution 0.5 hr — — — 19 20 — — (% Released) 1 hr — — — 3030 — — (n = 3) 2 hr — — — 48 51 — — 4 hr — — — 73 78 — — 8 hr — — — 9999 — — 12 hr — — — 99 102 — — n = 1 1 1 1 1 1 Post Hammer Test³ — 1.462.18 2.45 2.23 2.38 2.42 (10 strikes applied 1.19 2.20 2.34 2.39 2.262.40 manually) 1.24 2.18 2.03 2.52 2.50 2.16 Thickness (mm) ¹Tabletsmashed and crumbled during the breaking strength test ²196+ means thatsubjected to the maximum force of 196 Newton the tablets did not break.³The tablets flattened but did not break apart, hammering imparted someedge splits.

Example 5

In Example 5 three further tablets including 10% (by wt) of oxycodoneHCl were prepared.

Compositions:

Example 5.1 Example 5.2 Example 5.3 mg/unit mg/unit mg/unit Tablet (%)(%) (%) Oxycodone HCl 12 20 12 (10) (10) (10) Polyethylene Oxide 106.8178 82.8 (MW: approximately (89) (89) (69) 4,000,000; Polyox ™ WSR 301)Polyethylene Oxide 0 0 24 (1MW; approximately (20) 100,000; Polyox ™N10) Magnesium Stearate 1.2 2.0 1.2 (1) (1) (1) Total 120 200 120 TotalBatch size (kg) 100 100 100 (amount manufactured) Coating mg/unitmg/unit mg/unit Opadry white film 3.6 6.0 3. coating concentrate (3) (3)(3) formula Y-5-18024-A

The processing steps to manufacture tablets were as follows:

-   1. The polyethylene oxide was passed through a Sweco Sifter equipped    with a 20 mesh screen, into separate suitable containers.-   2. A Gemco “V” blender (with I bar)—10 cu. ft. was charged in the    following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride\

Polyethylene oxide N10 (only Example 5.3)

Remaining polyethylene oxide WSR 301

-   3. Step 2 materials were blended for 10 minutes (Example 5.1) or 20    minutes (Example 5.2) and 15 minutes (Example 5.3) with the I bar    on.-   4. Magnesium stearate was charged into the Gemco “V” blender.-   5. Step 4 materials were blended for 3 minutes with the I bar off.-   6. Step 5 blend was charged into clean, tared, stainless steel    containers.-   7. Step 5 blend was compressed to target weight on a 40 station    tablet press at 135,000 tph speed using 9/32 standard round, concave    (plain) tooling.-   8. Step 7 tablets were loaded into a 48 inch Accela-Coat coating pan    at 7 rpm at a pan load of 98.6 kg (Example 5.1), 92.2 kg (Example    5.2) and 96.9 kg (Example 5.3) and the tablet bed was heated using    an exhaust air temperature to achieve approximately 80° C. (Example    5.2 and 5.3) and 75° C. (Example 5.1) inlet temperature and cured    for 1 hour at the target inlet temperature.-   9. The pan speed was continued at 7 to 10 rpm and the tablet bed was    cooled using an exhaust air temperature to achieve a 25° C. inlet    temperature until the bed temperature achieves 30-34° C.-   10. The tablet bed was warmed using an exhaust air temperature to    achieve a 55° C. inlet temperature. The film coating was started    once the outlet temperature approached 39° C. and continued until    the target weight gain of 3% was achieved.-   11. After coating was completed, the pan speed was set to 1.5 rpm    and the exhaust temperature was set to 27° C., the airflow was    maintained at the current setting and the system cooled to an    exhaust temperature of 27-30° C.-   12. The tablets were discharged.

In vitro testing including testing for tamper resistance (breakingstrength and hammer test) and resistance to alcohol extraction wereperformed as follows:

Tablets cured at 0.5 hours and tablets cured at 1.0 hour and coated weretested in vitro using USP Apparatus 1 (basket) at 100 rpm in 900 mlsimulated gastric fluid without enzymes (SGF) at 37° C., using anAgilent UV/VIS Spectrometer Model HP8453, UV wavelength at 220 nM.Tablet dimensions and dissolution results corresponding to therespective curing time and temperature are presented in Tables 5.1 to5.3.

Tablets cured at 1.0 hour and coated were tested in vitro usingethanol/SGF media at a concentration of 40% ethanol to evaluate alcoholextractability. Testing was performed using USP Apparatus 1 (basket) at100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°C., using an Agilent UV/VIS Spectrometer Model HP8453, UV wavelength at230 nM. Tablet dissolution results are presented in Table 5.3.

As a further tamper resistance test, the uncured tablets and curedtablets were subjected to a breaking strength test applying a force of amaximum of 439 Newton using a Schleuniger Model 6D apparatus to evaluatethe resistance to breaking. The results are provided in Tables 5.1 to5.3.

Additionally, the tablets were flattened with a hammer using 10 manuallyconducted hammer strikes to impart physical tampering (hammer test).

TABLE 5.1 Example 5.1 1 hr cure/ 30 min cure coated Uncured (n = 10) (n= 10) Tablet Weight (mg) 119.7 ¹ 120 122 Dimensions Thickness (mm)  3.63² 3.91 3.88 Diameter (mm) — 7.03 7.02 Breaking strength (N)   54 ³ 439 ⁴438 ⁴ diameter (mm) post breaking — 4.18 4.26 strength Curing 10 min —75.8 75.8 Process 20 min — 75.1 75.1 Inlet 30 min — 76.0 76.0 Temp ° C.40 min — — 74.5 50 min — — 73.5 60 min — — 75.6 Dissolution 0.5 hr — 1919 (% Released)   1 hr — 31 33 (n = 3)   2 hr — 47 50   4 hr — 71 76   8hr — 93 97  12 hr — 99 102 Hammer Test — pre post pre post (10 strikesapplied manually) Tablet thickness measured 3.90 1.77 3.87 2.09 (mm) preand post test (n = 3) ¹ Fourteen in-process samples taken (40 tabletsper each sample) and each sample averaged. The reported value is theaverage of the averages. ² n = 39 ³ n = 130 ⁴ n = 10; The tablets didnot break when subjected to a maximum force of 438 N/439 N.

TABLE 5.2 Example 5.2 1 hr cure/ 30 min cure coated Uncured (n = 10) (n= 10) Tablet Weight (mg) 200.4 ¹ 201 206 Dimensions Thickness (mm)  5.50² 5.92 5.86 Diameter (mm) — 7.03 7.01 Breaking   85 ³ 439 ⁴ 439 ⁴strength (N) diameter (mm) — 5.52 5.72 post breaking strength Curing 10min — 79.7 79.7 Process 20 min — 80.3 80.3 Inlet 30 min — 79.3 79.3 Temp° C, 40 min — — 79.5 50 min — — 80.9 60 min — — 81.0 Dissolution 0.5 hr— 14 15 (% Released)   1 hr — 23 24 (n = 3)   2 hr — 36 38   4 hr — 5760   8 hr — 83 85  12 hr — 94 95 Hammer Test — pre post pre post (10strikes applied manually) 5.92 2.97 5.91 2.84 Tablet thickness measured(mm) pre and post test (n = 3) ¹ Nine in-process samples taken (40tablets per each sample) and each sample averaged. The reported value isthe average of the averages. ² n = 27 ³ n = 90 ⁴ n = 10; The tablets didnot break when subjected to a maximum force of 438 N/439 N.

TABLE 5.3 Example 5.3 1 hr cure/ 30 min cure coated Uncured (n = 10) (n= 10) Tablet Weight (mg) 120.5 ¹ 122 125 Dimensions Thickness (mm)  3.64² 3.85 3.77 Diameter (mm) — 7.03 7.01 Breaking   56 ³ 438 ⁴ 439 ⁴strength (N) diameter (mm) — 3.96 4.28 post breaking strength Curing 10min — 80.0 80.0 Process 20 min — 82.3 82.3 Inlet 30 min — 78.9 78.9 Temp° C. 40 min — — 79.5 50 min — — 79.5 60 min — — 80.7 40% SGF SGF EtOHDissolution 0.5 hr — 20 23 21 (% Released)   1 hr — 31 37 31 (n = 3)   2hr — 50 58 50   4 hr — 76 86 76   8 hr — 95 100 99  12 hr — 98 100 104Hammer Test — pre post pre post (10 strikes applied manually) 3.81 1.633.79 1.62 Tablet thickness measured (mm) pre and post test (n = 3) ¹Twelve in-process samples taken (40 tablets per each sample) and eachsample averaged. The reported value is the average of the averages. ² n= 33 ³ n = 130 ⁴ n = 10; The tablets did not break when subjected to amaximum force of 438 N/439 N.

Example 6

In Example 6 tablets comprising Naltrexone HCl were prepared.

Compositions:

mg/ unit Tablet Naltrexone HCl 10 Polyethylene Oxide 89.0 (MW:approximately 4,000,000; Polyox ™ WSR 301) Magnesium Stearate 1.0 Total100 Total Batch size (kg) 20 (amount manufactured) Coating Base coat 3.0Opadry Red film coating concentration formula Y-5-1-15139 Specialeffects 3.0 overcoat Opadry FX-Silver formula 62W28547

The tablets were prepared as outlined in Example 5, wherein a Gemco “V”blender (with I bar)—2 cu. ft, a 8 station rotary tablet press set at24,000 tph speed with a 9/32 standard round concave (embossedupper/plain lower) tooling and a 24 inch Compu-Lab coater were used. Theblending lime in step 2 was 8 minutes, the pan load was 9.2 kg and thecuring time 2 hours.

Example 7

Three further examples comprising each 10 mg of oxycodone hydrochloridewere manufactured and tested.

Compositions:

Example 7.1 Example 7.2 Example 7.3 Tablet mg/unit (%) mg/unit (%)mg/unit (%) Oxycodone HCl 10 (5)    10 (6.67) 10 (10) Polyethylene Oxide188 (94)  138.5 (92.3)  69 (69) (MW: approximately 4,000,000; Polyox ™WSR 301) Polyethylene Oxide 0 0 20 (20) (MW; approximately 100,000;Polyox ™ N10) Magnesium Stearate 2 (1) 1.5 (1)   1 (1) Total 200 150 100Total Batch size (kg) 100 100 100 (amount manufactured) Film Coatingmg/unit mg/unit mg/unit Opadry white film coating 6 4.5 3 concentrateformula Y-5-18024- AThe processing steps to manufacture tablets were as follows:

-   1. The magnesium stearate was passed through a Sweco Sifter equipped    with a 20 mesh screen, into separate suitable containers.-   2. A Gemco “V” blender (with I bar)—10 cu. ft. was charged in the    following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Polyethylene oxide N10 (only Example 7.3)

Remaining polyethylene oxide WSR 301

-   3. Step 2 materials were blended for 10 minutes with the I bar on.-   4. Magnesium stearate was charged into the Gemco “V” blender.-   5. Step 4 materials were blended for 3 minutes with the I bar off.-   6. Step 5 blend was charged into clean, tared, stainless steel    containers.-   7. Step 5 blend was compressed to target weight on a 40 station    tablet press at 135,000 tph speed using 9/32 inch standard round,    concave (plain) tooling (Example 7.1 and 7.2) and using ¼ inch    standard round, concave (plain) tooling (Example 7.3).-   8. Step 7 tablets were loaded into a 48 inch Accela-Coat coating pan    at a load of 97.388 kg (Example 7.1), 91.051 kg (Example 7.2) and    89.527 kg (Example 7.3).-   9. The pan speed was set to 7 rpm and the tablet bed was heated by    setting the exhaust air temperature to achieve an inlet temperature    of approximately 75° C. The tablets were cured at the target inlet    temperature for 1 hour (Example 7.1 and 7.2) and for 30 minutes    (Example 7.3).-   10. The pan speed was continued at 6 to 8 rpm and the tablet bed was    cooled using an exhaust air temperature to achieve a 25° C. inlet    temperature until the exhaust temperature achieves 30-34° C.-   11. The tablet bed was warmed using an exhaust air temperature to    target a 55° C. inlet temperature. The film coating was started once    the outlet temperature approached 39° C. and continued until the    target weight gain of 3% was achieved.-   12. After coating was completed, the pan speed was set to 1.5 rpm    and the exhaust temperature was set to 27° C., the airflow was    maintained at the current setting and the system cooled to an    exhaust temperature of 27-30° C.-   13. The tablets were discharged.

In vitro testing including testing for tamper resistance (breakingstrength, hammer test and flattened tablets) and resistance to alcoholextraction, as well as stability tests were performed as follows:

Cured, coated tablets (whole and flattened) were tested in vitro usingUSP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37° C. Samples were analyzed by reversed-phasehigh performance liquid chromatography (HPLC) on Waters Atlantis dC183.0×150 mm, 3 μm column, using a mobile phase consisting of a mixture ofacetonitrile and non basic potassium phosphate buffer (pH 3.0) at 230 nmUV detection. Sample time points include 0.5, 0.75, 1.0, 1.5 and 2.0hours. Additionally sample time points include 1.0, 4.0 and 12 hours.

Cured, coated tablets (whole and flattened) were tested in vitro usingethanol/SGF media at concentrations of 0% and 40% to evaluate alcoholextractability. Testing was performed using USP Apparatus 1 (basket) at100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°C. Samples were analyzed by reversed-phase high performance liquidchromatography (HPLC) on Waters Atlantis dC18 3.0×150 mm, 3 m column,using a mobile phase consisting of a mixture of acetonitrile and nonbasic potassium phosphate buffer (pH 3.0) at 230 nm UV detection. Sampletime points include 0.5, 0.75, 1.0, 1.5 and 2.0 hours.

Cured tablets were subjected to a breaking strength test by applying aforce of a maximum of 439 Newton using a Schleuniger Model 6D apparatusto evaluate tablet resistance to breaking.

Cured tablets were subject to a high amount of pressure using a Carvermanual bench press (hydraulic unit model #3912) to impart physicaltampering by flattening the tablets.

Cured tablets were subjected to a further breaking strength test by themanual application of 10 hammer strikes to impart physical tampering.

Cured, coated tablets were subjected to a stability test by storing themin 100 count bottles at different storage conditions (25° C./60%relative humidity or 40° C./75% relative humidity) for a certain periodof time and subsequently testing the tablets in vitro as describedabove. Sample time points regarding storage include initial sample (i.e.prior to storage), one month, two months, three months and six months ofstorage, sample time points regarding dissolution test include 1.0, 4.0and 12.0 hours.

Cured, coated tablets were subjected to a further stability test bystoring them in 100 count bottles at different storage conditions (25°C./60% relative humidity or 40° C./75% relative humidity) for a certainperiod of time and subsequently subjecting the tablets to the assay testto determine the content of oxycodone HCl in the tablet samples, inpercent relative to the label claim. Sample time points regardingstorage include initial sample (i.e. prior to storage), one month, twomonths, three months and six months of storage. In the assay test,oxycodone hydrochloride was extracted from two sets of ten tablets eachwith 900 mL of a 1:2 mixture of acetonitrile and simulated gastric fluidwithout enzyme (SGF) under constant magnetic stirring in a 1000-mLvolumetric flask until all tablets were completely dispersed or forovernight. The sample solutions were diluted and analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC₁₈ 3.0×250 mm, 5 μm column maintained at 60° C. using amobile phase consisting of acetonitrile and potassium phosphatemonobasic buffer at pH 3.0 with UV detection at 280 nm.

Cured, coated tablets were subjected to a further stability test bystoring them in 100 count bottles at different storage conditions (25°C./60% relative humidity or 40° C./75% relative humidity) for a certainperiod of time and subsequently subjecting the tablets to theoxycodone-N-oxide (ONO) test to determine the content of the degradationproduct oxycodone-N-oxide in percent relative to the oxycodone HCl labelclaim. Sample time points regarding storage include initial sample (i.e.prior to storage), one month, two months, three months and six months ofstorage. In the ONO test, oxycodone hydrochloride and its degradationproducts were extracted from a set of ten tablets with 900 mL of a 1:2mixture of acetonitrile and simulated gastric fluid without enzyme (SGF)under constant magnetic stirring in a 1000-mL volumetric flask until alltablets were completely dispersed or for overnight. The sample solutionswere diluted and analyzed by reversed-phase high performance liquidchromatography (HPLC) on Waters Atlantis dC₁₈ 3.0×250 mm, 5 μm columnmaintained at 60° C. using a mobile phase consisting of acetonitrile andpotassium phosphate monobasic buffer at pH 3.0 with UV detection at 206nm.

The results are presented in Tables 7.1 to 7.3

TABLE 7.1.1 Example 7.1 Flattened (n = 3) Whole (n = 10) (15,000 lbsapplied) Tablet Weight (mg) 205 207 204 Dimensions Thickness (mm) 5.95 1.01¹ 0.961 % Thickness 17.0 16.1 Diameter (mm) 7.02 17.13 ² 17.35 ²Breaking ≧438³ strength (N) Diameter (mm) post Breaking 5.84 strengthpre post Hammer Test 6.04 2.96 pre and post 5.95 3.10 tablet thickness6.03 3.32 measured (mm) Whole Flattened Whole 40% Flattened 40% SGF EtOHSGF EtOH Dissolution  0.5 hr 11  9 17 13 (% 0.75 hr 15 12 23 18Released)  1.0 hr 20 16 28 21 (n = 3)  1.5 hr 27 21 36 29  2.0 hr 34 2744 35 Whole 0.5 hr — Dissolution   1 hr 22 (%   2 hr — Released)   4 hr57 (n = 6)   8 hr —  12 hr 97 ¹3 measurements per tablet ² 2measurements per tablet ³tablets did not break when subjected to themaximum force of 438 Newton

TABLE 7.1.2 Stability tests Example 7.1 Storage conditions (° C./% RH)and storage time¹ 1 Mo 2 Mo 3 Mo 3 Mo Initial 40/75 40/75 25/60 40/75Dissolution (% 1 hr 22 21 21 20 21 Released) 4 hr 57 57 58 56 58 (n = 6)12 hr  97 98 98 97 97 SGF Assay test Assay 1 96.6 96.2 97.3 97.1 95.0 (%oxycodone Assay 2 95.3 97.2 95.7 98.7 96.0 HCl)² Average 96.0 96.7 96.597.9 95.5 ONO test 0.02 0.06 0.06 0.04 0.05 (% oxycodone N-oxide)² ¹[Mo= month(s)]; ²relative to the label claim of oxycodone HCl.

TABLE 7.2.1 Example 7.2 Flattened (n = 3) Whole (n = 10) (20,000 lbsapplied) Weight (mg) 154 154 153 Thickness (mm) 4.68  0.75¹  0.77¹ %Thickness 16.0 16.5 Tablet Diameter (mm) 7.02 17.14 ² 16.90 ² DimensionsBreaking 438³ strength (N) Diameter (mm) 4.93 post Breaking strength prepost Hammer Test 4.73 2.65 pre and post 4.64 2.95 tablet thicknessmeasured (mm) 4.67 2.60 Whole Flattened Whole 40% Flattened 40% SGF EtOHSGF EtOH Dissolution  0.5 hr 14 10 21 15 (% 0.75 hr 19 14 27 20Released)  1.0 hr 24 17 33 26 (n = 3)  1.5 hr 33 23 44 36  2.0 hr 40 2953 43 Whole Dissolution  0.5 hr — (%   1 hr 26 Released)   2 hr — (n =6)   4 hr 67   8 hr —   12 hr 98 ¹3 measurements per tablet ² 2measurements per tablet

TABLE 7.2.2 Stability tests Example 7.2 Storage conditions (° C./% RH)and storage time¹ 1 Mo 2 Mo 3 Mo 3 Mo 6 Mo 6 Mo Initial 40/75 40/7525/60 40/75 25/60 40/75 Dissolution 1 hr 26 24 22 23 24 25 25 (% 4 hr 6766 61 65 64 64 69 Released) 12 hr  98 101 97 98 99 99 97 (n = 6) SGFAssay test Assay 1 97.1 97.7 96.4 98.4 97.3 96.3 94.1 (% Assay 2 96.696.6 96.2 98.0 96.9 96.3 94.2 oxycodone Average 96.9 97.1 96.3 98.2 97.196.3 94.2 HCl)² ONO test 0.02 0.08 0.04 0.03 0.04 0.06 0.26 (% oxycodoneN-oxide)² ¹[Mo = month(s)]; ²relative to the label claim of oxycodoneHCl.

TABLE 7.3.1 Example 7.3 Flattened (n = 3) Whole (n = 10) (15,000 lbsapplied) Tablet Weight (mg) 103 102 104 Dimen- Thickness (mm) 3.92 0.61¹  0.66¹ sions (15.6) (16.8) Diameter (mm) 6.25 15.36 ² 15.24 ²Breaking strength 4393 (N) Diameter (mm) post 3.80 Breaking strength Prepost Hammer Test 3.90 1.66 pre and post 3.89 1.97 tablet thickness 3.911.56 measured (mm) Whole Flattened Whole 40% Flattened 40% SGF EtOH SGFEtOH Dissolution  0.5 hr 19 15 26 19 (% 0.75 hr 25 20 34 25 Released) 1.0 hr 30 25 40 31 (n = 3)  1.5 hr 41 33 51 41  2.0 hr 50 41 60 50Whole Dissolution  0.5 hr (%   1 hr 32 Released)   2 hr — (n = 6)   4 hr83   8 hr —  12 hr 101 ¹3 measurements per tablet ² 2 measurements pertablet ³The tablets did not break when subjected to the maximum force of439 Newton.

TABLE 7.3.2 Stability tests Example 7.3 Storage conditions (° C./% RH)and storage time¹ 1 Mo 2 Mo 3 Mo Initial 40/75 40/75 25/60 Dissolution(%  1 hr 32 29 30 31 Released)  4 hr 83 76 77 78 (n = 6) 12 hr 101 103102 103 SGF Assay test Assay 1 99.4 99.4 97.3 101.0 (% oxycodone Assay 298.8 98.9 100.0 101.0 HCl)² Average 99.1 99.1 98.6 101.0 ONO test 0.050.01 0.01 0.02 (% oxycodone N-oxide)² ¹[Mo = month(s)]; ²relative to thelabel claim of oxycodone HCl

Example 8

Two further 160 mg oxycodone hydrochloride tablets (Examples 8.1 and8.2) were manufactured.

Compositions:

Example 8.1 Example 8.2 Ingredient mg/unit % mg/unit % Oxycodone 160 25160 25 Hydrochloride Polyethylene Oxide 476.8 74.5 284.8 44.5 (high MW,grade 301) Polyethylene Oxide 0 0 192 30 (low MW, grade N10) MagnesiumStearate 3.2 0.5 3.2 0.5 Total 640 100 640 100The processing steps to manufacture tablets were as follows:

-   1. Oxycodone HCl and Polyethylene Oxide were dry mixed in a low/high    shear Black & Decker Handy Chopper dual blade mixer with a 1.5 cup    capacity for 30 seconds.-   2. Magnesium Stearate was added and mixed with the step 1 blend for    additional 30 seconds-   3. Step 2 blend was compressed to target weight on a single station    tablet Manesty Type F 3 press using a capsule shaped tooling    (7.937×14.290 mm).-   4. Step 2 tablets were placed onto a tray placed in a Hotpack model    435304 oven at 73° C. for 3 hours to cure the tablets.

In vitro testing including testing for tamper resistance (breakingstrength test) was performed as follows:

The tablets were tested in vitro using USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.,using an Agilent UV/VIS Spectrometer Model HP8453, UV wavelength at 280nM, after having been subjected to curing for 3 hours. Tablet dimensionsof the uncured and cured tablets and dissolution results are presentedin Table 8.

As a further tamper resistance test, the cured and uncured tablets weresubjected to a breaking strength test applying a force of a maximum of196 Newton using a Schleuniger 2E/106 Apparatus to evaluate theresistance to breaking. The results are presented in Table 8.

Additionally, the tablets were flattened with a hammer using 10 manuallyconducted hammer strikes to impart physical tampering (hammer test).Results are presented in Table 8.

TABLE 8 Example 8.1 Example 8.2 Uncured 3 hr cure Uncured 3 hr cure (n =12) (n = 5) (n = 12) (n = 10) Tablet Weight (mg) 648 648 643 643Dimensions Thickness 7.07 7.42 7.01 7.20 (mm) Width (mm) 7.96 7.97 7.967.91 Breaking 196+ ¹ 196+ ¹ 196+ ¹ 196+ ¹ strength(N) (n = 2) (n = 1) (n= 2) (n = 2) Dissolution 0.5 hr Not tested 9 Not 13 (%   1 hr 15 tested21 Released)   2 hr 23 35   4 hr 38 59   8 hr 60 89  12 hr 76 92 PostHammer Test Readily — Readily 3.80 (10 strikes applied broke brokemanually) apart apart Thickness (mm) ¹ The hardness tester would max at20+ Kp equivalent to 196+ Newtons (1 Kp = 9.807 Newtons), the tabletsdid not break when subjected to the maximum force of 196 N.

Example 9

Three examples comprising each 12 mg of hydromorphone hydrochloride weremanufactured and tested.

Compositions:

Example 9.1 Example 9.2 Example 9.3 Tablet mg/unit mg/unit mg/unitHydromorphone HCl 12 12 12 Polyethylene Oxide 483 681 829.5 (MW:approximately 7,000,000; Polyox ™ WSR 303) Magnesium Stearate 5 7 8.5Total 500 700 850 Total Batch size (kg) 100 100 100 (amountmanufactured) Film Coating mg/unit mg/unit mg/unit Magnesium Stearate0.100 0.142 0.170 Opadry white film 15 21 25.5 coating concentrateformula Y-5-18024-A Coating Batch Size (kg) 80 79 80The processing steps to manufacture tablets were as follows:

-   1. The Hydromorphone HCl and magnesium stearate were passed through    a Sweco Sifter equipped with a 20 mesh screen, into separate    suitable containers.-   2. A Gemco “V” blender (with I bar)—10 cu. ft. was charged in the    following order:

Approximately 25 kg of the polyethylene oxide WSR 303

Hydromorphone hydrochloride

Approximately 25 kg of the polyethylene oxide WSR 303

-   3. Step 2 materials were blended for 10 minutes with the I bar on.-   4. The remaining polyethylene oxide WSR 303 was charged into the    Gemco “V” blender.-   5. Step 4 materials were blended for 10 minutes with the I bar on.-   6. Magnesium stearate was charged into the Gemco “V” blender.-   7. Step 6 materials were blended for 3 minutes with the I bar off.-   8. Step 7 blend was charged into clean, tared, stainless steel    containers.-   9. Step 8 blend was compressed to target weight on a 40 station    tablet press at 133,000 tph speed using ½ inch standard round,    concave (plain) tooling.-   10. Step 9 tablets were loaded into a 48 inch Accela-Coat coating    pan at a load of 80 kg (Example 9.1 and 9.3) and 79 kg (Example    9.2).-   11. The pan speed was set to 2 rpm and the tablet bed was heated by    setting the exhaust air temperature to achieve a target inlet    temperature of approximately 75° C. The tablets were cured for 1    hour and 15 minutes at the following inlet temperature range,    75-87° C. (Example 9.1), 75-89° C. (Example 9.2) and 75-86° C.    (Example 9.3).-   12. At the onset of cooling the pan speed was increased to 7 rpm and    the tablet bed was cooled using an exhaust air temperature to    achieve a 25° C. inlet temperature until the exhaust temperature    achieves 30-34° C. During the cooling process, magnesium stearate    was added to the tablet bed to reduce tablet sticking.-   13. The tablet bed was warmed using an exhaust air temperature to    target a 55° C. inlet temperature. The film coating was started once    the outlet temperature approached 39° C. and continued until the    target weight gain of 3% was achieved.-   14. After coating was completed, the pan speed was set to 1.5 rpm    and the exhaust temperature was set to 27° C., the airflow was    maintained at the current setting and the system cooled to an    exhaust temperature of 27-30° C.-   15. The tablets were discharged.

Example 10

A further tablet comprising 12 mg of hydromorphone hydrochloride wasprepared.

Composition:

Example 10 Tablet mg/unit Hydromorphone HCl 12 Polyethylene Oxide 483(MW: approximately 7,000.000; Polyox ™ WSR 303) Magnesium Stearate 5Total 500 Total Batch size (kg) 119.98 (amount manufactured)

The processing steps to manufacture tablets were as follows:

-   1. The hydromorphone HCl and magnesium stearate were passed through    a Sweco Sifter equipped with a 20 mesh screen, into separate    suitable containers.-   2. A Gemco “V” blender (with I bar)—10 cu. ft. was charged in the    following order:

Approximately 60 kg of the polyethylene oxide WSR 303

Hydromorphone hydrochloride

-   3. Step 2 materials were blended for 10 minutes with the I bar on.-   4. The remaining polyethylene oxide WSR 303 was charged into the    Gemco “V” blender.-   5. Step 4 materials were blended for 10 minutes with the I bar on.-   6. Magnesium stearate was charged into the Gemco “V” blender.-   7. Step 6 materials were blended for 3 minutes with the I bar off.-   8. Step 7 blend was charged into clean, tared, stainless steel    containers.-   9. Step 8 blend was compressed to target weight on a 40 station    tablet press at 150,000 tph speed using ½ inch standard round,    concave (plain) tooling.-   10. Step 9 tablets were loaded into a 48 inch Accela-Coat coating    pan at a load of 92.887 kg.-   11. The pan speed was set to 1.9 rpm and the tablet bed was heated    by setting the exhaust air temperature to achieve a target inlet    temperature of approximately 80° C. The tablets were cured for 2    hours at the following inlet temperature range 80-85° C.-   12. At the end of curing and onset of cooling, the tablet bed began    to agglomerate (tablets sticking together). The pan speed was    increased up to 2.8 rpm, but the tablet bed fully agglomerated and    was non-recoverable for coating.

It is assumed that the agglomeration of tablets can be avoided, forexample by lowering the curing temperature, by increasing the pan speed,by the use of Magnesium Stearate as anti-tacking agent, or by applying asub-coating prior to curing.

However some tablets were sampled prior to cooling for In vitro testingwhich was performed as follows:

Cured tablets were tested in vitro using USP Apparatus 2 (paddle) at 75rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.using an on Waters Alliance System equipped with a Waters Novapak C₁₈3.9 mm×150 mm column, using a mobile phase consisting of a mixture ofacetonitrile, SDS, and mono basic sodium phosphate buffer (pH 2.9).Detection was done with a PDA detector. Sample time points include 1, 2,4, 8, 12, 18, and 22 hours.

TABLE 10 USP Apparatus 2 Dissolution  1 hr 19 (% Released)  2 hr 30 (n =6)  4 hr 48  8 hr 77 12 hr 95 18 hr 103 22 hr 104

Example 11

A further tablet comprising 12 mg of hydromorphone hydrochloride wasprepared.

Composition:

Tablet mg/unit Hydromorphone HCl 12 Polyethylene Oxide 681 (MW:approximately 7,000,000; Polyox ™ WSR 303) Magnesium Stearate 7 Total700 Total Batch size (kg) 122.53 (amount manufactured) Film Coatingmg/unit Opadry white film coating concentrate 21 formula Y-5-18024-ACoating Batch Size (kg) 80

The processing steps to manufacture tablets were as follows:

-   1. The hydromorphone HCl and magnesium stearate were passed through    a Sweco Sifter equipped with a 20 mesh screen, into separate    suitable containers.-   2. A Gemco “V” blender (with I bar)—10 cu. ft. was charged in the    following order:

Approximately 60 kg of the polyethylene oxide WSR 303

Hydromorphone hydrochloride

-   3. The remaining polyethylene oxide WSR 303 was charged into the    Gemco “V” blender.-   4. Step 4 materials were blended for 10 minutes with the I bar on.-   5. Magnesium stearate was charged into the Gemco “V” blender.-   6. Step 5 materials were blended for 3 minutes with the I bar off.-   7. Step 6 blend was charged into clean, tared, stainless steel    containers.-   8. Step 7 blend was compressed to target weight on a 40 station    tablet press at 150,000 tph speed using ½ inch standard round,    concave (plain) tooling.-   9. Step 8 tablets were loaded into a 48 inch Accela-Coat coating pan    at a load of 80.000 kg.-   10. The pan speed was set to 1.8 rpm and the tablet bed was heated    by setting the exhaust air temperature to achieve a target inlet    temperature of approximately 80° C. The tablets were cured for 1.25    hours at the following inlet temperature range 75-85° C.-   11. At the end of curing and onset of cooling, the tablet bed began    to agglomerate (tablets sticking together). The pan speed was    increased up to 10 rpm, and the tablets separated.-   12. The pan speed was continued at approximately 10 rpm and the    tablet bed was cooled using an exhaust air temperature to achieve a    25° C. inlet temperature until the exhaust temperature achieves    30-34° C.-   13. The tablet bed was warmed using an exhaust air temperature to    target a 55° C. inlet temperature. The film coating was started once    the outlet temperature approached 39° C. and continued until the    target weight gain of 3% was achieved.-   14. After coating was completed, the pan speed was set to 1.5 rpm    and the exhaust temperature was set to 27° C., the airflow was    maintained at the current setting and the system cooled to an    exhaust temperature of 27-30° C.-   15. The tablets were discharged.    In vitro testing was performed as follows:

Coated tablets were tested in vitro using USP Apparatus 2 (paddle) at

75 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.using an a Waters Alliance System equipped with a Waters Novapak C₁₈ 3.9mm×150 mm column, using a mobile phase consisting of a mixture ofacetonitrile, SDS, and mono basic sodium phosphate buffer (pH 2.9).Detection was done with a PDA detector. Sample time points include 1, 2,4, 8, 12, 18, 22, and 24 hours. The results are presented in Table 11.

TABLE 11 USP Apparatus 2 Dissolution  1 hr 12 (% Released)  2 hr 19(Mean n = 6)  4 hr 29  8 hr 46 12 hr 60 18 hr 76 22 hr 84 24 hr 88

Example 12

Two further examples comprising 10 mg of oxycodone hydrochloride whichinclude core tablets as presented in Example 2.3 were manufactured whichwere coated by a polyethylene oxide coating to provide a delay of therelease.

Composition: Core Tablet

Ingredient mg/unit Oxycodone HCl 10 Polyethylene Oxide 85 (MW:approximately 4,000,000; Polyox ™ WSR301) Hydroxypropyl Cellulose 5(Klucel ™ HXF) Total Tablet Core 100

Composition: Compression Coat Over Core Tablet

Example 12.1 Example 12.2 Ingredient mg/unit mg/unit Polyethylene Oxide200 100 ( MW: approximately 4,000,000; Polyox ™ WSR301) Core tablet 100100 Total Tablet Weight 300 200

Process of Manufacture:

The processing steps to manufacture tablets were as follows:

-   -   1. A tablet from Example 2.3 was used as the tablet core.    -   2. A single station Manesty Type F 3 tablet press was equipped        with 0.3125 inch, round, standard concave plain tooling.    -   3. For Example 12.1, approximately 100 mg of Polyethylene Oxide        was placed in the die, the tablet core was manually centered in        the die (on top of the powder bed), an additional 100 mg of        Polyethylene Oxide was placed on top of the tablet in the die.    -   4. The materials were manually compressed by turning the        compression wheel.    -   5. For Example 12.2, approximately 50 mg of Polyethylene Oxide        was placed in the die, the tablet core was manually centered in        the die (on top of the powder bed), an additional 50 mg of        Polyethylene Oxide was placed on top of the tablet in the die.    -   6. The materials were manually compressed by turning the        compression wheel.    -   7. Step 4 and step 6 tablets were placed onto a tray placed in a        Hotpack model 435304 oven targeting 75° C. for 3 hours to cure        the compression coated tablets.

In vitro testing was performed as follows:

The tablets were tested in vitro using USP Apparatus 1 (basket) at 100rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.,using a Perkin Elmer UV/VIS Spectrometer Lambda 20 USP Apparatus, UV at220 nM. The cured compression coated tablet dimensions and dissolutionresults are presented in Table 12.

TABLE 12 Example 12.1 Example 12.2 Tablet Weight (mg) 304 312 209 210Dimensions Thickness (mm) 5.62 5.73 5.24 5.29 Diameter (mm) 9.10 9.107.61 7.54 Dissolution 0.5 hr 0 1 (% Released)   1 hr 0 15 (n = 2)   2 hr1 47   4 hr 9 95   8 hr 82 96  12 hr 97 96

Example 13

In Example 13, five different 156 mg tablets (Examples 13.1 to 13.5)including 10, 15, 20, 30 and 40 mg of Oxycodone HCl were prepared usinghigh molecular weight polyethylene oxide.

Compositions:

Example Example Example Example Example 13.1 13.2 13.3 13.4 13.5Ingredient mg/unit mg/unit mg/unit mg/unit mg/unit Oxycodone HCl 10 1520 30 40 Polyethylene 138.5 133.5 128.5 118.5 108.5 oxide (MW:approximately 4,000,000; Polyox ™ WSR-301) Magnesium 1.5 1.5 1.5 1.5 1.5Stearate Total Core 150 150 150 150 150 Tablet Weight (mg) Total Batchsize 10 kg 10 kg 10 kg 10 kg 10 kg Coating mg/unit mg/unit mg/unitmg/unit mg/unit Opadry film 6 6 6 6 6 coating Total Tablet 156 156 156156 156 Weight (mg) Coating Batch 8.754 9.447 9.403 8.717 8.902 Size(kg)The processing steps to manufacture tablets were as follows:

-   1. A Patterson Kelly “V’ blender (with I bar)—16 quart was charged    in the following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Remaining polyethylene oxide WSR 301

-   2. Step 1 materials were blended for 5 minutes with the I bar on.

3. Magnesium stearate was charged into the “V” blender.

-   4. Step 3 materials were blended for 1 minute with the I bar off.-   5. Step 4 blend was charged into a plastic bag.-   6. Step 5 blend was compressed to target weight on an 8 station    tablet press at 35,000 tph speed using 9/32 inch standard round,    concave (embossed) tooling.-   7. Step 6 tablets were loaded into a 24 inch Compu-Lab coating pan    at a pan load of 8.754 kg (Example 13.1), 9.447 kg (Example 13.2),    9.403 kg (Example 13.3), 8.717 kg (Example 13.4), 8.902 kg (Example    13.5).-   8. A temperature probe (wire thermocouple) was placed into the pan    directly above the tablet bed so that the probe tip was near the    moving bed of tablets.-   9. The pan speed was set to 7 rpm and the tablet bed was heated by    setting the inlet temperature to achieve a probe target temperature    of 75° C. The curing starting point (as described by method 4) was    initiated once the temperature probe indicated approximately 70° C.    (Example 13.1 at 68.3° C., Example 13.2 at 69.9° C., Example 13.3    and 13.4 at 70.0° C., and Example 13.5 at 71.0° C.). Once the target    probe temperature was achieved, the inlet temperature was adjusted    as necessary to maintain this target probe temperature. The tablets    were cured for 90 minutes. The pan speed was increased to 12 rpm at    approximately 60 minutes of curing (except for Example 13.5, the pan    speed was maintained at 7 rpm throughout curing). Samples were taken    after 30 minutes, 60 minutes and 90 minutes of curing. The    temperature profile of the curing processes for Examples 13.1 to    13.5 is presented in Tables 13.1.1 to 13.5.1 and in FIGS. 10 to 14.-   10. At the end of curing, magnesium stearate was added to the moving    be of tablets as an anti-tacking agent. The amount of magnesium    stearate added was 8.75 g (Example 13.1), 1.8887 g (Example 13.2),    1.8808 g (Example 13.3), 1.7400 g (Example 13.4), and 1.784 g    (Example 13.5). The magnesium stearate was weighed in a weigh boat    and was applied by manually dispensing (dusting) the powder across    the moving tablet bed. The pan speed was continued at 12 rpm    (Example 13.5 at 7 rpm) and the tablet bed was cooled by setting the    inlet temperature to 21° C. The tablet bed was cooled to an exhaust    temperature of <41° C.-   11. The tablet bed was warmed using an inlet setting of 55° C. The    film coating was started once the exhaust temperature achieved    approximately 43° C. and continued until the target weight gain of    4% was achieved.-   12. After film coating was completed, the pan speed was reduced (3    to 6 rpm) and the inlet temperature was set to 21° to 25° C. to cool    the system, the airflow was maintained at the current setting.-   13. The tablets were discharged.

In vitro testing including breaking strength tests and densitymeasurement was performed as follows:

Tablets cured for 30 minutes and 60 minutes, and tablets cured for 90minutes and coated were tested in vitro using USP Apparatus 1 (basket)at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at37° C.

Samples were analyzed by reversed-phase high performance liquidchromatography (HPLC) on Waters Atlantis dC18 3.0×150 mm, 3 μm column,using a mobile phase consisting of a mixture of acetonitrile and nonbasic potassium phosphate buffer (pH 3.0) at 230 nm UV detection. Sampletime points include 1.0, 2.0, 4.0, 8.0 and 12.0 hours. Tablet dimensionsand dissolution results corresponding to the respective curing time andtemperature are presented in Tables 13.1.2 to 13.5.2.

Uncured tablets, cured tablets and cured, coated tablets were subjectedto a breaking strength test by applying a force of a maximum of 439Newton using a Schleuniger Model 6D apparatus to evaluate tabletresistance to breaking or to a breaking strength test applying a forceof a maximum of 196 Newton using a Schleuniger 2E/106 Apparatus toevaluate the resistance to breaking.

The density of uncured tablets and tablets cured for different periodsof time (30, 60 and 90 minutes samples) was determined by Archimedesprinciple, using a Top-loading Mettler Toledo balance Model #AB135-S/FACT, Serial #1127430072 and a density determination kit 33360,according to the following procedure:

-   1. Set-up the Mettler Toledo balance with the Density Determination    Kit.-   2. Fill an appropriately sized beaker (200 ml) with hexane.-   3. Weigh the tablet in air and record the weight as Weight A.-   4. Transfer the same tablet onto the lower coil within the beaker    filled with hexane.-   5. Determine the weight of the tablet in hexane and record the    weight as Weight B.-   6. Perform the density calculation according to the equation

${\rho = {\frac{A}{A - B} \cdot \rho_{0}}},$

wherein

-   -   ρ: Density of the tablet    -   A: Weight of the tablet in air    -   B: Weight of the tablet when immersed in the liquid    -   ρ₀: Density of the liquid at a given temperature (density of        hexane at 20° C.=0.660 g/ml (Merck Index)

-   7. Record the density.    The reported density values are mean values of 3 tablets and all    refer to uncoated tablets.

The results are presented in the following Tables.

TABLE 13.1.1 Temperature profile of the curing process for Ex. 13.1Total Curing Set inlet Actual inlet Probe Exhaust Time time temperaturetemperature temperature temperature (min.) (min.)¹ (° C.) (° C.)² (°C.)³ (° C.)⁴ Comments 0 — 27 26.9 26.8 25.7 10 — 75 74.9 59.5 56.8 15 085 84.8 68.3 65.5 Curing starts 20 5 85 84.7 71 68.4 26 11 85 84.8 72.870.1 30 15 85 84.8 74 70.9 45 30 83 83 74.8 74.7 30 min sample 55 40 8181.2 74.8 76 61 46 81 81.2 74.7 75.9 65 50 81 81 74.8 75.8 70 55 81 8174.7 75.8 75 60 81 81.1 75 75.9 60 min sample 85 70 81 81.1 74.6 75.8 9580 81 81.1 74.8 75.9 105 90 81 80.9 74.9 76 End of curing, 90 min sample112 — 21 35.3 49 55.6 128 — 21 33.4 32 — ¹determined according to method4, ²temperature measured at the inlet; ³temperature measured using thetemperature probe (wire thermocouple) ⁴temperature measured at theexhaust.

TABLE 13.1.2 Example 13.1 30 min 60 min 90 min cure, Uncured cure curecoated (n = 5) (n = 5) (n = 5) (n = 5) Tablet Weight (mg) 153 153 152158 Dimen- Thickness (mm) 4.63 4.98 4.89 4.89 sions Diameter (mm) 7.147.00 6.98 6.98 Breaking 80 196 ¹ 196 ¹ 438 ² strength (N) n = 3 n = 3 n= 6 Disso-  1 hr —  25 (9.5)  24 (8.4)  27 (7.3) lution  2 hr —  39(7.7)  39 (8.7)  43 (6.6) (%  4 hr —  62 (7.0)  62 (5.8)  67 (6.8)Released)  8 hr —  89 (4.7)  91 (5.0)  92 (2.9) SGF 12 hr — 100 (3.3)100 (3.6) 101 (2.4) ¹ maximum force of the hardness tester, the tabletsdid not break when subjected to the maximum force of 196N. ² maximumforce of the hardness tester, the tablets did not break when subjectedto the maximum force of 438N.

TABLE 13.2.1 Temperature profile of the curing process for Ex. 13.2Total Curing Set inlet Actual inlet Probe Exhaust Time time temperaturetemperature temperature temperature (min.) (min.)¹ (° C.) (° C.)² (°C.)³ (° C.)⁴ Comments 0 — 23 22.7 26.1 23.8 5 — 85 81 55.7 51.1 10 — 8585.1 63.7 62.3 21  0 85 84.8 69.9 69.1 Curing starts 31 10 85 85.1 72.470.9 41 20 85 85.1 73.7 72.5 51 30 82 82 74.8 75.8 30 min sample 61 4082 81.9 75 76.2 71 50 81 81 74.8 75.9 81 60 81 80.8 75 75.9 60 minsample 91 70 81 81 74.9 76 101 80 80.5 80.5 74.8 75.8 111 90 80.5 80.574.8 75.7 End of curing, 90 min sample 118 — 21 23.1 50 55.1 131 — 2122.4 34.1 37.7 ¹determined according to method 4, ²temperature measuredat the inlet; ³temperature measured using the temperature probe (wirethermocouple), ⁴temperature measured at the exhaust.

TABLE 13.2.2 Example 13.2 30 min 60 min 90 min cure, Uncured cure curecoated (n = 5) (n = 5) (n = 5) (n = 5) Tablet Weight (mg) 152 153 152157 Dimen- Thickness (mm) 4.69 4.99 4.90 4.84 sions Diameter (mm) 7.146.98 6.95 6.95 Breaking 62 196 ¹ 196 ¹ 196 ¹ strength (N) n = 6 n = 6 n= 6 Disso-  1 hr —  23 (10.6)  22 (8.5) 25 (5.2) lution  2 hr —  38(10.1)  37 (7.7) 41 (4.6) (%  4 hr —  64 (9.5)  61 (8.1) 65 (3.6)Released)  8 hr —  92 (6.8)  90 (4.6) 91 (2.4) SGF 12 hr — 100 (3.4) 100(3.2) 99 (2.9) ¹ maximum force of the hardness tester, the tablets didnot break when subjected to the maximum force of 196N.

TABLE 13.3.1 Temperature profile of the curing process for Ex. 13.3:Total Curing Set inlet Actual inlet Probe Exhaust Time time temperaturetemperature temperature temperature (min.) (min.)¹ (° C.) (° C.)² (°C.)³ (° C.)⁴ Comments 0 — 25 24.9 27.8 26.2 5 — 90 85 58.2 53.9 10 — 9089.8 67 65.1 13  0 90 90.1 70 68.3 Curing starts 23 10 90 90 74.6 72.233 20 86 85.9 74.7 73.4 43 30 83 83.1 75.4 76.5 30 min sample 53 40 8282.1 74.9 76.3 63 50 81.5 81.8 75 76.4 73 60 81.5 81.5 74.7 76.1 60 minsample 83 70 81.5 81.5 75 76.1 93 80 81.5 81.6 75 76.1 103 90 81.5 81.375 76.1 End of curing, 90 min sample 109 — 21 35.5 50 57.5 121 — 21 22.633.8 39.3 ¹determined according to method 4, ²temperature measured atthe inlet; ³temperature measured using the temperature probe (wirethermocouple), ⁴temperature measured at the exhaust.

TABLE 13.3.2 Example 13.3 30 min 60 min 90 min cure, Uncured cure curecoated (n = 5) (n = 5) (n = 5) (n = 5) Tablet Weight (mg) 154 154 152160 Dimensions Thickness (mm) 4.56 4.85 4.79 4.77 Diameter (mm) 7.137.01 6.96 6.98 Breaking 83 196 ¹ 196 ¹ 196 ¹ strength (N) n = 6 n = 6 n= 6 Dissolution  1 hr — 22 (5.8)  26 (9.2)  23 (5.7) (%  2 hr — 37 (6.4) 42 (8.6)  39 (4.7) Released)  4 hr — 61 (6.3)  67 (6.3)  64 (3.7) SGF 8 hr — 90 (4.5)  93 (3.3)  92 (2.7) 12 hr — 99 (3.1) 101 (2.2) 101(1.8) ¹ maximum force of the hardness tester, the tablets did not breakwhen subjected to the maximum force of 196N.

TABLE 13.4.1 Temperature profile of the curing process for Ex. 13.4:Total Curing Set inlet Actual inlet Probe Exhaust Time time temperaturetemperature temperature temperature (min.) (min.)¹ (° C.) (° C.)² (°C.)³ (° C.)⁴ Comments 0 — 25 25 24.6 23.4 5 — 90 85 46.8 51 10 — 90 89.956.6 63.8 15 — 90 89.8 68.5 68.7 16  0 90 90.1 70 69.5 Curing starts 2610 90 90 73.6 72.9 36 20 86 86 75.4 76.8 46 30 84 84 75.4 77.2 30 minsample 56 40 83 82.9 75.1 76.8 66 50 82 81.4 74.8 76.6 76 60 82 81.774.7 76.3 60 min sample 86 70 82 82.1 75 76.3 96 80 82 82.1 75.1 76.3106 90 82 82.1 75.1 76.4 End of curing, 90 min sample 112 — 21 33.8 55.950 126 — 21 22.1 31.6 34.6 ¹determined according to method 4,²temperature measured at the inlet; ³temperature measured using thetemperature probe (wire thermocouple), ⁴temperature measured at theexhaust.

TABLE 13.4.2 Example 13.4 30 min 60 min 90 min cure, Uncured cure curecoated (n = 5) (n = 5) (n = 5) (n = 5) Tablet Weight (mg) 150 151 150159 Dimensions Thickness (mm) 4.43 4.73 4.67 4.68 Diameter (mm) 7.137.00 6.97 7.00 Breaking 65 196 ¹ 196 ¹ 196 ¹ strength (N) n = 6 n = 6Dissolution  1 hr — 29 (3.2)  25 (7.9)  24 (5.5) (%  2 hr — 47 (3.1)  42(6.7)  41 (5.2) Released)  4 hr — 71 (2.4)  67 (5.2)  67 (6.2) SGF  8 hr— 92 (2.5)  92 (4.3)  94 (3.2) 12 hr — 99 (2.1) 100 (2.8) 101 (2.2) ¹maximum force of the hardness tester, the tablets did not break whensubjected to the maximum force of 196N.

TABLE 13.5.1 Temperature profile of the curing process for Ex. 13.5:Total Curing Set inlet Actual inlet Probe Exhaust Time time temperaturetemperature temperature temperature (min.) (min.)¹ (° C.) (° C.)² (°C.)³ (° C.)⁴ Comments 0 — 80 69.2 39.8 35.6 10 — 90 80.2 64.9 65.6 20 090 90.2 70.9 71 Curing starts 25 5 90 89.9 71.7 72.4 30 10 90 90.1 72.873.4 35 15 85 87.1 74.1 76.1 50 30 85 85 75.2 77.5 30 min sample 60 4083 83.2 74.7 76.8 80 60 83 83.1 75.1 76.5 60 min sample 90 70 83 83 75.376.6 100 80 80 79.1 74.4 76 110 90 80 80.1 73.6 74.7 End of curing, 90min sample 115 — 21 39.6 55.6 59.4 120 — 21 24.5 41.5 45.2 125 — 21 2337.7 40.7 ¹determined according to method 4, ²temperature measured atthe inlet; ³temperature measured using the temperature probe (wirethermocouple), ⁴temperature measured at the exhaust.

TABLE 13.5.2 Example 13.5 90 min 30 min 60 min 90 min cure, Uncured curecure cure coated (n = 5) (n = 5) (n = 5) (n = 5) (n = 5) Tablet Weight(mg) 156 157    154    153    158    Dimensions Thickness (mm) 4.45 4.664.57 4.52 4.51 Diameter (mm) 7.12 7.06 7.04 7.03 7.08 Breaking 90438¹     438¹     438¹     438¹     strength (N) Relaxed diameter — 4.574.68 4.69 4.67 (mm) post breaking strength test (NLT 15 min relaxperiod) n = 6 n = 6 Dissolution 1 hr — 28 (5.0) 29 (5.9) — 26 (1.4) (% 2hr — 45 (5.2) 45 (5.6) — 42 (1.4) Released) 4 hr — 69 (4.8) 70 (4.4) —68 (2.0) SGF 8 hr — 93 (4.2) 94 (4.0) — 94 (4.0) 12 hr  — 98 (3.9) 102(5.2)  — 99 (5.1) ¹maximum force of the hardness tester, the tablets didnot break when subjected to the maximum force of 438 N.

TABLE 13.6 Density (g/cm³)¹ Density 30 min 60 min 90 min change afterUncured cure cure cure curing (%)² Example 13.1 1.172 1.131 1.134 1.137−2.986 Example 13.2 1.174 1.137 1.137 1.140 −2.896 Example 13.3 1.1791.151 1.152 1.152 −2.290 Example 13.4 1.182 1.167 1.168 1.172 −0.846Example 13.5 1.222 1.183 1.183 1.187 −2.864 ¹ The density value is amean value of 3 tablets measured; ² The density change after curingcorresponds to the observed density change in % of the tablets cured for90 min in comparison to the uncured tablets.

Example 14

In Example 14, five different 156 mg tablets (Examples 14.1 to 14.5)including 10, 15, 20, 30 and 40 mg of oxycodone HCl were prepared usinghigh molecular weight polyethylene oxide, in a larger batch sizecompared to Example 13.

Compositions:

Example Example Example Example Example 14.1 14.2 14.3 14.4 14.5Ingredient mg/unit mg/unit mg/unit mg/unit mg/unit Oxycodone HCl 10 1520 30 40 Polyethylene oxide 138.5 133.5 128.5 118.5 108.5 (MW:approximately 4,000,000; Polyox ™ WSR- 301) Magnesium Stearate 1.5 1.51.5 1.5 1.5 Total Core Tablet 150 150 150 150 150 Weight (mg) TotalBatch size 100 kg 100 kg 100 kg 100 kg 100 kg Coating mg/unit mg/unitmg/unit mg/unit mg/unit Opadry film coating 6 6 6 6 6 Total TabletWeight 156 156 156 156 156 (mg) Coating Batch Size 97.480 98.808 97.86499.511 98.788 (kg)The processing steps to manufacture tablets were as follows:

-   1. The magnesium stearate was passed through a Sweco Sifter equipped    with a 20 mesh screen, into a separate suitable container.-   2. A Gemco “V” blender (with I bar) 10 cu. ft. was charged in the    following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Remaining polyethylene oxide WSR 301

-   3. Step 2 materials were blended for 10 minutes with the I bar on.-   4. Magnesium stearate was charged into the Gemco “V” blender.-   5. Step 4 materials were blended for 3 minutes with the I bar off.-   6. Step 5 blend was charged into clean, tared, stainless steel    containers.-   7. Step 6 blend was compressed to target weight on a 40 station    tablet press at 135,000 tph using 9/32 inch standard round, concave    (embossed) tooling.-   8. Step 7 tablets were loaded into a 48 inch Accela-Coat coating pan    at a load of 97.480 kg (Example 14.1), 98.808 kg (Example 14.2),    97.864 kg (Example 14.3), 99.511 kg (Example 14.4) and 98.788 kg    (Example 14.5).-   9. The pan speed was set to 7 rpm and the tablet bed was heated by    setting the exhaust air temperature to achieve an inlet air    temperature of 75° C. The tablets were cured at the target inlet    temperature for 1 hour (Examples 14.1 to 14.5). The starting point    used for the determination of the curing time according to method 1    was the point when the inlet temperature achieved the target    temperature of 75° C. The temperature profile of the curing    processes of Examples 14.1 to 14.5 is presented in Tables 14.1.1 to    14.5.1 and in FIGS. 15 to 19.-   10. The pan speed was continued at 7 rpm for Examples 14.2, 14.4 and    14.5. The pan speed was increased up to 10 rpm for Example 14.1 and    up to 8 rpm for Example 14.3. For Examples 14.2 to 14.5, 20 g of    magnesium stearate was added as an anti-tacking agent. The tablet    bed was cooled by slowly lowering the exhaust temperature setting    (Example 14.1) or by immediately setting the exhaust temperature    setting to 25° C. (Example 14.2) or 30° C. (Examples 14.3 to 14.5).    until a specific exhaust temperature of 30 to 34° C. was reached.-   11. The tablet bed was warmed using an exhaust air temperature to    target a 55° C. inlet temperature. The film coating was started once    the exhaust temperature approached 39° C. and continued until the    target weight gain of 4% was achieved.-   12. After coating was completed, the pan speed was set to 1.5 rpm    and the exhaust temperature was set to 27° C., the airflow was    maintained at the current setting and the system cooled to an    exhaust temperature of 27-30° C.-   13. The tablets were discharged.

In vitro testing including breaking strength tests and stability testswas performed as follows:

Tablets cured for 1 hour and coated were tested in vitro using USPApparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37° C. Samples were analyzed by reversed-phasehigh performance liquid chromatography (HPLC) on Waters Atlantis dC183.0×150 mm, 3 μm column, using a mobile phase consisting of a mixture ofacetonitrile and non basic potassium phosphate buffer (pH 3.0) at 230 nmUV detection. Sample time points include 1.0, 2.0, 4.0, 6.0, 8.0 and12.0 hours. Tablet dimensions and dissolution results corresponding tothe respective curing time and temperature are presented in Tables14.1.2 to 14.5.2.

Uncured tablets were subjected to a breaking strength test by applying aforce of a maximum of 196 Newton using a Schleuniger 2E/106 Apparatus toevaluate tablet resistance to breaking.

Cured, coated tablets were subjected to a stability test by storing themin 100 count bottles at different storage conditions (25° C./60%relative humidity or 40° C./75% relative humidity) for a certain periodof time and subsequently testing the tablets in vitro as describedabove. Sample time points regarding storage include initial sample (i.e.prior to storage), one month, two months, three months and six months ofstorage, sample time points regarding dissolution test include 1.0, 2.0,4.0, 8.0 and 12.0 hours.

Cured, coated tablets were subjected to a further stability test bystoring them in 100 count bottles at different storage conditions (25°C./60% relative humidity or 40° C./75% relative humidity) for a certainperiod of time and subsequently subjecting the tablets to the assay testto determine the content of oxycodone HCl in the tablet samples. Sampletime points regarding storage include initial sample (i.e. prior tostorage), one month, two months, three months and six months of storage.In the assay test, oxycodone hydrochloride was extracted from two setsof ten tablets each with 900 mL of a 1:2 mixture of acetonitrile andsimulated gastric fluid without enzyme (SGF) under constant magneticstirring in a 1000-mL volumetric flask until all tablets were completelydispersed or for overnight. The sample solutions were diluted andanalyzed by reversed-phase high performance liquid chromatography (HPLC)on Waters Atlantis dC₁₈ 3.0×250 mm, 5 μm column maintained at 60° C.using a mobile phase consisting of acetonitrile and potassium phosphatemonobasic buffer at pH 3.0 with UV detection at 280 nm.

Cured, coated tablets were subjected to a further stability test bystoring them in 100 count bottles at different storage conditions (25°C./60% relative humidity or 40° C./75% relative humidity) for a certainperiod of time and subsequently subjecting the tablets to theoxycodone-N-oxide (ONO) test to determine the content of the degradationproduct oxycodone-N-oxide and unknown degradation products in percent byweight, relative to the oxycodone HCl label claim. Sample time pointsregarding storage include initial sample (i.e. prior to storage), onemonth, two months, three months and six months of storage. In the ONOtest, oxycodone hydrochloride and its degradation products wereextracted from a set of ten tablets with 900 mL of a 1:2 mixture ofacetonitrile and simulated gastric fluid without enzyme (SGF) underconstant magnetic stirring in a 1000-mL volumetric flask until alltablets were completely dispersed or for overnight. The sample solutionswere diluted and analyzed by reversed-phase high performance liquidchromatography (HPLC) on Waters Atlantis dC₁₈ 3.0×250 mm, 5 μm columnmaintained at 60° C. using a mobile phase consisting of acetonitrile andpotassium phosphate monobasic buffer at pH 3.0 with UV detection at 206nm.

The density of uncured tablets, cured tablets and cured/coated tabletswas determined as described for Example 13.

The results are presented in the following Tables.

TABLE 14.1.1 Temperature profile of the curing process for Ex. 14.1 SetActual Total Curing Inlet exhaust exhaust Pan time time temp. temp.temp. speed (min.) (min.)¹ (° C.)² (° C.) (° C.)³ (rpm) Comments 0 — — —— 7 Load pan, start warming 20 — 65 57 56 7 21 — 65.0 7 28 — 70.0 7 30 —72.0 64 63 7 36  0 75.0 65 65 7 Curing starts 0 min sample 43  7 73.2 746 10 73 67 67 51 15 72.2 7 15 min sample 56 20 71.8 67 67 8 66 30 75.068 68 8 30 min sample 76 40 73.0 68 68 8 81 45 74.8 8 45 min sample 8650 74.3 69 69 8 92 56 72.3 8 96 60 71.0 69 69 8 End of curing, 60 minsample, Mg stearate not used, start cool down, tablet flow was sticky101 — 62.0 8 Tablet flow starting to get chunky 104 — 59.2 9 Flow verychunky (tablet bed “sheeting”) 106 — 57 62 62 10 109 — 54.9 9 Tabletflow still slightly chunky, but better 110 — 53.2 8 Back to normaltablet flow 116 — 48.0 58 58 8 126 — 29.0 30 46 7 132 — 24.0 30 33 7¹determined according to method 1, ²temperature measured at the inlet,³temperature measured at the exhaust.

TABLE 14.1.2 Example 14.1 60 min cure, 60 min cure coated Uncured (n =5) (n = 5) Tablet Weight (mg) 150 150 158  Dimensions (n = 120)Thickness (mm) 4.42 (n = 5)    4.71    4.75 Diameter (mm) 7.14 (n = 5)   7.05    7.07 Breaking  68  196¹ 196¹  strength (N) (n = 100) n = 6Dissolution  1 hr — — 25 (%  2 hr — — 42 Released)  4 hr — — 67 SGF  8hr — — 94 12 hr — — 101  ¹maximum force of the hardness tester, thetablets did not break when subjected to the maximum force of 196N.

TABLE 14.1.3 Stability tests Example 14.1, storage at 25° C./60% RHStorage time Initial 1 month 2 months 3 months 6 months Dissolution 1 hr25 24 24 23 23 (% Released) 2 hr 42 40 38 38 39 (n = 6 4 hr 67 64 61 6164 SGF 8 hr 94 90 87 89 90 12 hr  101 99 94 100 97 Assay test Assay 19.8 9.8 9.8 9.8 9.7 (mg oxycodone Assay 2 9.8 9.9 9.8 9.9 9.8 HCl)Average 9.8 9.8 9.8 9.9 9.8 Degradation oxycodone N-oxide ≦0.1 ≦0.1 ≦0.1≦0.1 ≦0.1 products test (%)¹ Each individual ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1unknown (%)¹ Total degradation ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 products (%)¹¹relative to the label claim of oxycodone HCl.

TABLE 14.1.4 Stability tests Example 14.1, storage at 40° C./75% RHStorage time Initial 1 month 2 months 3 months 6 months Dissolution 1 hr25 25 25 24 23 (% Released) 2 hr 42 — 41 38 39 (n = 6) 4 hr 67 66 63 6264 SGF 8 hr 94 — 89 88 90 12 hr  101 100 96 98 96 Assay test Assay 1 9.89.8 9.7 9.6 9.8 (mg oxycodone Assay 2 9.8 10.0 9.7 9.8 9.8 HCl) Average9.8 9.9 9.7 9.7 9.8 Degradation oxycodone N-oxide ≦0.1 ≦0.1 ≦0.1 ≦0.1≦0.1 products test (%)¹ Each individual ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 unknown(%)¹ Total degradation ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 products (%)¹ ¹relativeto the label claim of oxycodone HCl.

TABLE 14.2.1 Temperature profile of the curing process for Ex. 14.2 SetActual Total Curing Inlet exhaust exhaust Pan time time temp. temp.temp. speed (min.) (min.)¹ (° C.)² (° C.) (° C.)³ (rpm) Comments 0 — 1850 20 7 Load pan, start warming 1 — 41.0 7 5 — 50.0 62.0 8 — 67.7 51.050.5 7 Slowly adjusting exhaust set 10 — 71 56 55 14 0 75.0 61.7 61.9 7curing starts, 0 min sample 19 5 77.2 61.7 64.8 7 21 7 77.8 7 Highinlet, then dropped to 71° C. 24 10 68.9 65.3 65.3 7 29 15 70.6 66.165.5 7 15 min sample 33 19 72.6 7 34 20 73.6 67.0 66.3 7 36 22 75.0 7 3925 75.9 67.0 67.3 7 44 30 73.3 67.0 67.4 7 30 min sample 49 35 70.1 67.267.0 7 54 40 71.7 67.5 67.3 7 Couple of tablets sticking at pan supportarms, no permanent stick 59 45 74.3 68.0 67.9 7 45 min sample 64 50 7568 68 7 66 52 73.6 68.0 68.2 7 69 55 72.4 68.0 68.1 7 74 60 73.0 68 68 7End of curing, 60 min sample, add 20 g Mg stearate, tablet flow wasslightly sticky (based on visual cascade flow), flow instantly improvedafter adding Mg stearate 75 — 73 25 68 7 Normal tablet flow observed 78— 44.7 25 62.3 7 during cool down 81 — 36.8 25 57.4 7 84 — 31.8 25 54.67 85 — 30 25 53 7 94 — 23 25 33 7 ¹determined according to method 1,²temperature measured at the inlet, ³temperature measured at theexhaust.

TABLE 14.2.2 Example 14.2 60 min cure, 60 min cure coated Uncured (n =5) (n = 5) Tablet Weight (mg) 150 149 156 Dimensions (n = 120) Thickness(mm)  4.38 (n = 5)  4.68  4.70 Diameter (mm)  7.13 (n = 5)  7.07  7.09Breaking  70 196 ¹ 196 ¹ strength (N) (n = 100) n = 6 Dissolution  1 hr— —  23 (%  2 hr — —  39 Released)  4 hr — —  64 SGF  8 hr — —  93 12 hr— — 100 ¹ maximum force of the hardness tester, the tablets did notbreak when subjected to the maximum force of 196 N.

TABLE 14.2.3 Stability tests Example 14.2, storage at 25° C./60% RHStorage time 2 3 6 Initial 1 month months months months Dissolution 1 hr23 24 26 22 24 (% Released) 2 hr 39 40 41 37 40 (n = 6) 4 hr 64 65 65 6165 SGF 8 hr 93 91 90 90 91 12 hr  100 100 97 99 99 Assay test Assay 114.6 14.9 14.6 14.7 14.8 (mg Assay 2 14.8 14.9 14.7 14.8 14.9 oxycodoneAverage 14.7 14.9 14.7 14.7 14.8 HCl) Degradation oxycodone ≦0.1 ≦0.1≦0.1 ≦0.1 ≦0.1 products test N-oxide (%)¹ Each ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1individual unknown (%)¹ Total ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 degradationproducts (%)¹ ¹relative to the label claim of oxycodone HCl.

TABLE 14.2.4 Stability tests Example 14.2, storage at 40° C./75% RHStorage time 2 3 6 Initial 1 month months months months Dissolution 1 hr23 25 26 22 24 (% Released) 2 hr 39 41 42 36 40 (n = 6) 4 hr 64 66 66 5865 SGF 8 hr 93 94 92 87 91 12 hr  100 102 97 97 98 Assay test Assay 114.6 14.8 14.7 14.6 14.9 (mg Assay 2 14.8 14.8 14.7 14.5 14.7 oxycodoneAverage 14.7 14.8 14.7 14.5 14.8 HCl) Degradation oxycodone ≦0.1 ≦0.1≦0.1 ≦0.1 ≦0.1 products test N-oxide (%)¹ Each ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1individual unknown (%)¹ Total ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 degradationproducts (%)¹ ¹relative to the label claim of oxycodone HCl.

TABLE 14.3.1 Temperature profile of the curing process for Ex. 14.3 SetActual Total Curing Inlet exhaust exhaust Pan time time temp. temp.temp. speed (min.) (min.)¹ (° C.)² (° C.) (° C.)³ (rpm) Comments 0 —17.1 50 18 7 Load pan, start warming 5 — 61.0 50 42.5 7 10 — 70.2 5655.8 7 15 0 75.0 61.6 61.9 7 Curing starts, 0 min sample 20 5 78.5 62.865.4 7 22 7 79.0 62.8 66.3 7 Inlet high 25 10 69.7 65.6 65.6 7 30 1568.4 66.0 65.3 7 15 min sample 35 20 72.4 66.7 66.1 7 40 25 75.6 67.567.3 7 45 30 76.9 68.0 67.9 7 30 min sample 55 40 73.0 68.4 68.2 7 60 4573.9 68.6 68.4 7 45 min sample 65 50 75 68.9 68.8 7 68 53 — — — 7 Coupleof tablets (1-4) sticking at pan support arms, good tablet flow 70 5576.2 69.6 69.6 8 75 60 77.0 70.5 70.8 8 End of curing, 60 min sample,add 20 g Mg stearate, tablet flow instantly improved 76 — 76 30 71 8Normal tablet flow observed 79 — 43.9 30 60.6 8 during cool down 85 —31.1 30 54.1 8 No sticking 86 — 30 30 53 8 96 — 23 30 33 8 ¹determinedaccording to method 1, ²temperature measured at the inlet, ³temperaturemeasured at the exhaust.

TABLE 14.3.2 Example 14.3 60 min cure, 60 min cure coated Uncured (n =5) (n = 5) Tablet Weight (mg) 150 150 156 Dimensions (n = 120) Thickness(mm)  4.38 (n = 5)  4.69  4.67 Diameter (mm)  7.14 (n = 5)  7.08  7.10Breaking  64 196 ¹ 196 ¹ strength (N) (n = 110) n = 6 Dissolution  1 hr— —  24 (%  2 hr — —  41 Released)  4 hr — —  66 SGF  8 hr — —  92 12 hr— —  98 ¹ maximum force of the hardness tester, the tablets did notbreak when subjected to the maximum force of 196 N.

TABLE 14.3.3 Stability tests Example 14.3, storage at 25° C./60% RHStorage time Initial 1 month 2 months 3 months 6 months Dissolution 1 hr24 25 22 24 21 (% Released) 2 hr 41 42 38 40 38 (n = 6) 4 hr 66 69 61 6663 SGF 8 hr 92 96 89 91 88 12 hr  98 102 97 99 96 Assay test Assay 119.6 19.4 19.5 19.4 19.8 (mg oxycodone Assay 2 19.4 19.3 19.4 19.4 19.4HCl) Average 19.5 19.4 19.4 19.4 19.6 Degradation oxycodone N-oxide ≦0.1≦0.1 ≦0.1 ≦0.1 ≦0.1 products test (%)¹ Each individual ≦0.1 ≦0.1 ≦0.1≦0.1 ≦0.1 unknown (%)¹ Total degradation ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1products (%)¹ ¹relative to the label claim of oxycodone HCl.

TABLE 14.3.4 Stability tests Example 14.3, storage at 40° C./75% RHStorage time 2 3 6 Initial 1 month months months months Dissolution 1 hr24 27 24 23 22 (% Released) 2 hr 41 44 40 39 40 (n = 6) 4 hr 66 70 63 6365 SGF 8 hr 92 94 90 89 90 12 hr  98 102 98 98 98 Assay test Assay 119.6 19.3 19.6 19.3 19.7 (mg Assay 2 19.4 19.3 19.7 19.4 19.4 oxycodoneAverage 19.5 19.3 19.6 19.4 19.6 HCl) Degradation oxycodone ≦0.1 ≦0.1≦0.1 ≦0.1 ≦0.1 products test N-oxide (%)¹ Each ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1individual unknown (%)¹ Total ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 degradationproducts (%)¹ ¹relative to the label claim of oxycodone HCl.

TABLE 14.4.1 Temperature profile of the curing process for Ex. 14.4 SetActual Total Curing Inlet Bed exhaust exhaust time time temp. temp.temp. temp. (min.) (min.)¹ (° C.)² (° C.)³ (° C.) (° C.)⁴ Comments⁵ 0Load pan, start warming 3 63.0 46.5 50.0 41.2 5 66.7 49.9 50.0 48.0 10 075.0 60.5 60.0 59.0 curing starts, 0 min sample 14 4 78.4 65.2 61.5 63.615 5 79.1 66.0 61.5 64.5 20 10 67.6 66.2 63.0 64.7 24 15 69.2 66.7 65.764.9 15 min sample 28 19 73.0 67.8 66.4 65.8 29 20 73.5 68.0 67.0 66.032 23 75.6 69.0 67.0 66.7 34 25 75.9 69.4 67.0 67.0 39 30 76.5 70.2 67.767.7 30 min sample 44 35 76.8 70.8 68.2 68.2 47 38 76.7 71.0 68.8 68.4Couple of tablets sticking at pan support arms, no permanent sticking 4940 77.4 71.0 69.3 68.7 52 43 78.7 71.5 69.5 69.2 54 45 79.1 72.1 70.069.5 45 min sample 58 49 — 73.3 — — 59 50 81.0 73.8 70.1 70.8 65 56 73.074.1 71.7 71.5 69 60 74.0 74.5 71.7 71.3 End of curing, 60 min sample,add 20 g Mg stearate, start cool down, tablet flow slightly sticky(based on visual cascade flow), still couple of tablets sticking atsupport arms, flow/cascade instantly improved after adding Mg stearate72 — 48.9 65.3 30.0 65.3 Normal tablet flow observed 75 — 39.7 58.6 30.056.8 during cool down 79 — 33.2 56.4 30.0 54.6 84 — 27.7 50.0 30.0 48.4¹determined according to method 1, ²temperature measured at the inlet,³tablet bed temperature, i.e. temperature of extended release matrixformulations, measured with an IR gun, ⁴temperature measured at theexhaust, ⁵The pan speed was 7 rpm throughout the curing process.

TABLE 14.4.2 Example 14.4 60 min cure, 60 min cure coated Uncured (n =5) (n = 5) Tablet Weight (mg) 150 149 157 Dimensions (n = 120) Thickness(mm)  4.34 (n = 5)  4.60  4.63 Diameter (mm)  7.14 (n = 5)  7.09  7.14Breaking  61 196 ¹ 196 ¹ strength (N) (n = 100) n = 6 Dissolution  1 hr— —  22 (%  2 hr — —  39 Released)  4 hr — —  66 SGF  8 hr — —  94 12 hr— — 100 ¹ maximum force of the hardness tester, the tablets did notbreak when subjected to the maximum force of 196 N.

TABLE 14.4.3 Stability tests Example 14.4, storage at 25° C./60% RHStorage time 2 3 6 Initial 1 month months months months Dissolution 1 hr22 23 24 24 23 (% Released) 2 hr 39 39 39 41 40 (n = 6) 4 hr 66 64 63 6865 SGF 8 hr 94 91 88 93 91 12 hr  100 98 96 99 98 Assay test Assay 128.8 28.8 28.4 28.8 29.2 (mg Assay 2 29.1 29.0 28.8 28.8 29.2 oxycodoneAverage 29.0 28.9 28.6 28.8 29.2 HCl) Degradation oxycodone ≦0.1 ≦0.1≦0.1 ≦0.1 ≦0.1 products test N-oxide (%)¹ Each ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1individual unknown (%)¹ Total ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 degradationproducts (%)¹ ¹relative to the label claim of oxycodone HCl.

TABLE 14.4.4 Stability tests Example 14.4, storage at 40° C./75% RHStorage time 2 3 6 Initial 1 month months months months Dissolution 1 hr22 26 24 24 24 (% Released) 2 hr 39 44 41 41 41 (n = 6) 4 hr 66 70 64 6767 SGF 8 hr 94 93 88 92 93 12 hr  100 99 96 98 98 Assay test Assay 128.8 29.3 28.2 29.0 28.4 (mg Assay 2 29.1 29.3 28.1 28.9 28.6 oxycodoneAverage 29.0 29.3 28.1 28.9 28.5 HCl) Degradation oxycodone ≦0.1 ≦0.1≦0.1 ≦0.1 ≦0.1 products test N-oxide (%)¹ Each ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1individual unknown (%)¹ Total ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 degradationproducts (%)¹ ¹relative to the label claim of oxycodone HCl.

TABLE 14.5.1 Temperature profile of the curing process for Ex. 14.5 SetActual Total Curing Inlet Bed exhaust exhaust time time temp. temp.temp. temp. (min.) (min.)¹ (° C.)² (° C.)³ (° C.) (° C.)⁴ Comments⁵  0 —16.6 30 60.0 19.7 Load pan, start warming  1 — — 32 60.0 —  4 — 56.839.8 60.0 36.7  5 — 60.1 43.9 60.0 40.4  8 — 66.8 52.5 60.0 49.4 10 —69.1 56.9 60.0 53.8 13 — 71.7 61.3 60.0 58.8 15 — 73.3 63.5 61.0 60.8 170 75.0 65.3 63.0 62.5 Curing starts, 0 min sample 21 4 77.7 67.3 66.065.0 23 6 78.8 68.1 67.0 65.9 25 8 79.9 69.3 67.0 66.7 27 10 80.9 69.567.0 67.3 30 13 82.4 70.1 67.0 68.2 32 15 83.1 70.8 70.0 68.7 15 minsample 37 20 80.9 72.4 70.4 69.4 38 21 80.9 71.8 71.0 69.5 42 25 82.573.1 72.0 70.4 Good tablet flow and cascade 45 28 84.2 76.6 71.0 72.2 4730 82.7 77.6 72.2 74.1 30 min sample 49 32 72.9 74.7 72.2 73.2 52 3571.2 73.8 72.2 71.4 Tablet flow slightly sticky, 1-2 tablets sticking atsupport arms 56 39 75.4 74.7 72.2 71.5 57 40 75.9 74.7 72.2 71.9 60 4376.9 75.5 72.2 72.8 62 45 75.4 75.3 72.2 72.9 45 min sample 66 49 73.474.5 72.2 71.8 Tablet flow slightly sticky, 1-2 tablets sticking atsupport arms (not permanent sticking) 69 52 75.0 75.1 72.2 71.9 72 5575.8 75.4 72.2 72.4 74 57 74.8 74.8 72.2 72.5 77 60 73.9 74.9 72.2 72.2End of curing, 60 min sample, add 20 g Mg stearate, instantly improvedflow/cascade start cool down, no sticking at pan support arms, 80 — 46.864.9 30.0 64.7 Cooling — — — — 30.0 — 2 tablets sticking at support arms(not permanent sticking) 82 — 40.3 58.6 30.0 57.4 Tablets still appearbouncy, no sticking observed 84 — 35.8 57.4 30.0 55.6 Normal tablet flowobserved 86 — 32.5 55.9 30.0 54.2 during cool down period. 87 — 30.354.1 30.0 52.8 Continue cooling to exhaust 89 — 28.8 51.8 30.0 51.3temperature of 30-34° C. for 91 — 26.9 47.2 30.0 47.9 coating start-up97 — — ~29 30.0 — Top of bed 30.3° C., bottom of bed 28.5° C.¹determined according to method 1, ²temperature measured at the inlet,³tablet bed temperature, i.e. temperature of extended release matrixformulations, measured with an IR gun, ⁴temperature measured at theexhaust, ⁵The pan speed was 7 rpm throughout the curing process.

TABLE 14.5.2 Example 14.5 60 min cure, 60 min cure coated Uncured (n =5) (n = 5) Tablet Weight (mg) 150 149 155 Dimensions (n = 120) Thickness(mm)  4.30 (n = 5)   4.49  4.52 Diameter (mm)  7.15 (n = 5)   7.10  7.15Breaking  55 196 ¹ 196 ¹ strength (N) (n = 110) n = 6 Dissolution  1 hr— —  24 (%  2 hr — —  41 Released)  4 hr — —  68 SGF  8 hr — —  93 12 hr— —  98 ¹ maximum force of the hardness tester, the tablets did notbreak when subjected to the maximum force of 196 N.

TABLE 14.5.3 Stability tests Example 14.5, storage at 25° C./60% RHStorage time 2 3 6 Initial 1 month months months months Dissolution 1 hr24 25 27 23 25 (% Released) 2 hr 41 43 44 40 43 (n = 6) 4 hr 68 69 69 6669 SGF 8 hr 93 94 93 89 92 12 hr  98 98 97 96 96 Assay test Assay 1 37.838.4 36.9 37.6 39.2 (mg Assay 2 37.9 37.6 36.5 38.1 39.2 oxycodoneAverage 37.8 38.0 36.7 37.9 39.2 HCl) Degradation oxycodone ≦0.1 ≦0.1≦0.1 ≦0.1 ≦0.1 products test N-oxide (%)¹ Each ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1individual unknown (%)¹ Total ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 degradationproducts (%)¹ ¹relative to the label claim of oxycodone HCl.

TABLE 14.5.4 Stability tests Example 14.5, storage at 40° C./75% RHStorage time 1 2 3 6 Initial month months months months Dissolution 1 hr24 26 27 25 25 (% Released) 2 hr 41 — 45 42 43 (n = 6) 4 hr 68 71 72 6869 SGF 8 hr 93 — 95 93 92 12 hr  98 97 98 99 95 Assay test Assay 1 37.838.3 37.3 37.6 37.9 (mg Assay 2 37.9 38.6 36.9 37.6 38.1 oxycodoneAverage 37.8 38.5 37.1 37.6 38.0 HCl) Degradation oxycodone ≦0.1 ≦0.1≦0.1 ≦0.1 ≦0.1 products test N-oxide (%)¹ Each ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1individual unknown (%)¹ Total ≦0.1 ≦0.1 ≦0.1 ≦0.1 ≦0.1 degradationproducts (%)¹ ¹relative to the label claim of oxycodone HCl.

TABLE 14.6 Density Density (g/cm³) change Cured Density after and changeafter curing and Uncured Cured Coated curing (%) coating (%) Example14.1 1.186 1.145 1.138 −3.457 −4.047 Example 14.2 1.184 1.152 1.129−2.703 −4.645 Example 14.3 1.183 1.151 1.144 −2.705 −3.297 Example 14.41.206 1.162 1.130 −3.648 −6.302 Example 14.5 1.208 1.174 1.172 −2.815−2.980

Example 15

In Example 15, two different Oxycodone HCl tablet formulations wereprepared using high molecular weight polyethylene oxide. One formulationat 234 mg tablet weight (Example 15.1) with 60 mg of Oxycodone HCl andone formulation at 260 mg tablet weight (Example 15.2) with 80 mg ofOxycodone HCl.

Compositions:

Example 15.1 Example 15.2 mg/unit mg/unit Ingredient Oxycodone HCl 60 80Polyethylene oxide (MW: approximately 162.75 167.5 4,000,000; Polyox ™WSR-301) Magnesium Stearate 2.25 2.50 Total Core Tablet Weight (mg) 225250 Total Batch size 10 kg 10 kg Coating Opadry film coating 9 10 TotalTablet Weight (mg) 234 260 Coating Batch Size (kg) 8.367 8.205The processing steps to manufacture tablets were as follows:

-   1. A Patterson Kelly “V’ blender (with I bar)—16 quart was charged    in the following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride (screened through a 20-mesh screen)

Remaining polyethylene oxide WSR 301

-   2. Step 1 materials were blended for 5 minutes with the I bar on.-   3. Magnesium stearate was charged into the “V” blender (screened    through a 20-mesh screen).-   4. Step 3 materials were blended for 1 minute with the I bar off.-   5. Step 4 blend was charged into a plastic bag (note: two 5 kg    blends were prepared to provide 10 kgs of tablet blend for    compression).-   6. Step 5 blend was compressed to target weight on an 8 station    tablet press at 35,000 tph speed using ⅜ inch standard round,    concave (embossed) tooling. A sample of tablet cores was taken.-   7. Step 6 tablets were loaded into a 24 inch Compu-Lab coating pan    at a pan load of 8.367 kg (Example 15.1) and 8.205 kg (Example    15.2).-   8. A temperature probe (wire thermocouple) was placed into the pan    directly above the tablet bed so that the probe tip was near the    cascading bed of tablets.-   9. The pan speed was set to 10 rpm and the tablet bed was heated by    setting the inlet temperature to achieve an exhaust target    temperature of 72° C. The curing starting point (as described by    method 2) was initiated once the exhaust temperature achieved 72° C.    The inlet temperature was adjusted as necessary to maintain the    target exhaust temperature. The tablets were cured for 15 minutes.    The pan speed was maintained at 10 rpm. The temperature profile of    the curing processes for Examples 15.1 and 15.2 is presented in    Tables 15.1.1 and 15.2.1.-   10. The pan speed was continued at 10 rpm. The inlet temperature was    set to 22° C. and the tablet bed was cooled until an exhaust    temperature of 30.0° C. was achieved. A sample of cured tablets was    taken at the end of cooling.-   11. The tablet bed was warmed using an inlet setting of 53° C. The    filmcoating was started once the exhaust temperature achieved    approximately 41° C. and continued until the target weight gain of    4% was achieved. The pan speed was increased up to 20 rpm during    filmcoating.-   12. After filmcoating was completed, the pan speed was reduced and    the inlet temperature was set to 22° C., the airflow was maintained    at the current setting and the system cooled to an exhaust    temperature of <30° C. A sample of cured/coated tablets was taken.-   13. The tablets were discharged.

In vitro testing including breaking strength tests was performed asfollows:

Core tablets (uncured), 15 minute cured tablets and cured/coated tabletswere tested in vitro using USP Apparatus 1 (basket with a retainingspring placed at the top of the basket to reduce the propensity of thetablet to slick to the base of the shaft) at 100 rpm in 900 nilsimulated gastric fluid without enzymes (SGF) at 37.0° C. Samples wereanalyzed by reversed-phase high performance liquid chromatography (HPLC)on Waters Atlantis dC18 3.0×250 mm, 5 μm column, using a mobile phaseconsisting of a mixture of acetonitrile and potassium phosphatemonobasic buffer (pH 3.0) at 230 nm UV detection. Sample time pointsinclude 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 16.0 hours.

Core tablets (uncured), 15 minute cured tablets and cured/coated tabletswere subjected to a breaking strength test by applying a force of amaximum of 196 Newton using a Schleuniger 2E/106 apparatus to evaluatetablet resistance to breaking.

Tablet dimensions and dissolution results are presented in Tables 15.1.2to 15.2.2.

TABLE 15.1.1 Temperature profile of the curing process for Ex. 15.1Total Curing Temperature Time time Set inlet Actual Probe Exhaust (min.)(min.)¹ (° C.) inlet (° C.)² (° C.)³ (° C.)⁴ Comments 0 — 22 to 85 47.4— 26.4 Start heating 10 — 85 81.3 66.3 62.0 20 — 85 84.8 73.7 70.4 Goodtablet flow, no sticking 25.5  0 85 to 74 85.0 75.1 72.0 Start ofcuring; 74° C. inlet set too low, exhaust dropped to 70.9° C., resetinlet to 80° C. 30.5  5 80 80.0 73.6 71.9 Good tablet flow, no sticking35.5 10 75 75.8 72.2 73.3 Good tablet flow, no sticking 40.5 15 73 to 2272.8 70.6 71.9 End of curing, good tablet flow, no sticking, startcooling 60 — 22 21.5 27.9 31.4 61 — 22 22.0 27.2 29.7 End cooling, nosticking observed during cool down, good tablet flow, take cured tabletsample ¹determined according to method 2, ²temperature measured at theinlet, ³temperature measured using the temperature probe (wirethermocouple) ⁴temperature measured at the exhaust.

TABLE 15.1.2 Example 15.1 Uncured 15 min cure Coated n = 3 n = 3 n = 6Dissolution  1 hr 28 28 24 (% Released)  2 hr 44 44 41 SGF  4 hr 69 6967  6 hr 85 85 84  8 hr 95 95 93 12 hr 102 102 99 16 hr 104 103 102

TABLE 15.2.1 Temperature profile of the curing process for Ex. 15.2Total Curing Temperature Time time Set inlet Actual Probe Exhaust (min.)(min.)¹ (° C.) inlet (° C.)² (° C.)³ (° C.)⁴ Comments 0 — 22 to 80 23.327.7 25.5 Start heating 10 — 80 77.0 62.2 60.4 20 — 80 80.0 70.1 68.4Good tablet flow, no sticking 30 — 80 80.1 72.5 70.6 Good tablet flow,no sticking 35 0 80 79.9 73.6 72.0 Start of curing; good tablet flow, nosticking 38 3 — — — 72.7 Maximum exhaust temp 40 5 74 73.5 71.8 72.3 4510  74 73.9 71.9 72.3 Good tablet flow, no sticking 50 15  74 to 22 74.272.0 72.4 End of curing, start cooling 71 — 22 21.7 28.4 30.0 Endcooling, no sticking observed during cool down, good tablet flow, takecured tablet sample ¹determined according to method 2, ²temperaturemeasured at the inlet, ³temperature measured using the temperature probe(wire thermocouple) ⁴temperature measured at the exhaust.

TABLE 15.2.2 Example 15.2 Uncured 15 min cure Coated (n = 25) (n = 5) (n= 5) Tablet Weight (mg) 254 250 257 Dimensions Thickness (mm) 4.20  4.28 4.29 Breaking strength (N) 92 196 ¹ 194 ² n = 3 n = 3 n = 6 Dissolution 1 hr 26  28  25 (% Released)  2 hr 43  42  39 SOF  4 hr 65  67  64  6hr 83  83  82  8 hr 92  94  92 12 hr 101 102 100 16 hr 104 103 102 ¹maximum force of the hardness tester, the tablets did not break whensubjected to the maximum force of 196 N. ² Four of the tablets did notbreak when subjected to the maximum force of 196 N, one tablet provideda breaking strength of 185 N (average of sample, n = 5,194 N).

Example 16

In Example 16, two different Oxycodone HCl tablet formulations wereprepared using high molecular weight polyethylene oxide. One formulationat 234 mg tablet weight (Example 16.1) with 60 mg of Oxycodone HCl andone formulation at 260 mg tablet weight (Example 16.2) with 80 mg ofOxycodone HCl. The formulations manufactured at a larger batch sizecompared to Example 15.

Compositions:

Example 16.1 Example 16.2 mg/unit mg/unit Ingredient Oxycodone HCl 60 80Polyethylene oxide (MW: approximately 162.75 167.5 4,000,000; Polyox ™WSR-301, LEO) Magnesium Stearate 2.25 2.50 Total Core Tablet Weight (mg)225 250 Total Batch size 100 kg 100 kg Coating Opadry film coating 9 10Total Tablet Weight (mg) 234 260 Coating Batch Size (kg) 94.122 93.530The processing steps to manufacture tablets were as follows:

-   1. The Oxycodone HCl and magnesium stearate were passed through a    Sweco Sifter equipped with a 20 mesh screen, into separate suitable    containers.-   2. A Gemco “V” blender (with I bar)—10 cu. ft. was charged in the    following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Remaining polyethylene oxide WSR 301

-   3. Step 2 materials were blended for 10 minutes with the I bar on.-   4. Magnesium stearate was charged into the Gemco “V” blender.-   5. Step 4 materials were blended for 2 minutes with the I bar off.-   6. Step 5 blend was charged into clean, tared, stainless steel    containers.-   7. Step 6 blend was compressed to target weight on a 40 station    tablet press at 135,000 tph speed using ⅜ inch standard round,    concave embossed tooling, and a compression force of 16.5 kN for    Example 16.1 and a compression force of 16.0 kN for Example 16.2. A    sample of core tablets was taken.-   8. Step 7 tablets were loaded into a 48 inch Accela-Coat coating pan    at a load of 94.122 kg (Example 16.1) and 93.530 kg (Example 16.2).-   9. The pan speed was set to 7 rpm and the tablet bed was heated by    setting the exhaust air temperature to achieve an exhaust    temperature of 72° C. The curing starting point (as described by    method 2) was initiated once the exhaust temperature achieved 72° C.    The tablets were cured at the target exhaust temperature for 15    minutes. The temperature profile of the curing processes of Examples    16.1 and 16.2 is presented in Tables 16.1.1 and 16.2.1.-   10. The pan speed was continued at 7 rpm. The exhaust temperature    was set to 25° C. and the tablet bed was cooled until an exhaust    temperature of 30° C. was achieved.-   11. The tablet bed was warmed using an exhaust setting of 30° to    38° C. The filmcoating was started once the exhaust temperature    achieved 40° C. and continued until the target weight gain of 4% was    achieved. The pan speed was maintained at 7 rpm during filmcoating.-   12. After filmcoating was completed, the pan speed was reduced to    1.5 rpm and the exhaust temperature was set to 27° C., the airflow    was maintained at the current setting and the tablet bed cooled to    an exhaust temperature of <30° C.-   13. The tablets were discharged.

In vitro testing including breaking strength tests was performed asfollows:

Coated tablets were tested in vitro using USP Apparatus 1 (basket with aretaining spring placed at the top of the basket to reduce thepropensity of the tablet to stick to the base of the shaft) at 100 rpmin 900 ml simulated gastric fluid without enzymes (SGF) at 37.0° C.Samples were analyzed by reversed-phase high performance liquidchromatography (HPLC) on Waters Atlantis dC18 3.0×250 mm, 5 μm column,using a mobile phase consisting of a mixture of acetonitrile andpotassium phosphate monobasic buffer (pH 3.0) at 230 nm UV detection.Sample time points include 1.0, 2.0, 4.0, 8.0, and 12.0 hours.

Uncured tablets were subjected to weight, thickness and hardness testson-line by Key Checkweigher.

Tablet dimensions and dissolution results are presented in Tables 16.1.2to 16.2.2.

TABLE 16.1.1 Temperature profile of the curing process for Ex. 16.1Total Curing Temperature Time time Inlet IR gun Exhaust Exhaust (min.)(min.)¹ (° C.)² (° C.)³ set (° C.) (° C.)⁴ Comments 0 — 34 32 65 24Start heating 5 — 82 54 65 49 10 — 89 68 65 63 11 — — — 72 — 15 — 91 7172 67 20 — 91 75 72 70 21  0 92 79 72 72 Start curing 26  5 90 85 70 7930  9 63 — — — 31 10 69 74 72 69 36 15 80 78 72 72 37 16 80 77 72 to 2573 End of curing, good tablet flow, no sticking, start cooling 42 — 3157 25 54 47 — 25 50 25 49 52 — 22 36 25 36 57 — 22 26 25 29 End cooling,no sticking observed during cool down, good tablet flow ¹determinedaccording to method 2, ²temperature measured at the inlet, ³temperaturemeasured using an IR gun ⁴temperature measured at the exhaust.

TABLE 16.1.2 Example 16.1 Uncured (n = 70) Coated Tablet DimensionsWeight (mg) 224.6 — Thickness (mm) 3.77 — Breaking strength (Kp) 5.7 — n= 6 Dissolution  1 hr — 24 (% Released)  2 hr — 41 SGF  4 hr — 67  8 hr— 93 12 hr — 99

TABLE 16.2.1 Temperature profile of the curing process for Ex. 16.2Total Curing Temperature Time time Inlet IR gun Exhaust Exhaust (min.)(min.)¹ (° C.)² (° C.)³ set (° C.) (° C.)⁴ Comments 0 — 26 22 20 23 2 —— — 20 to 65 — Start heating 7 — 84 61 65 56 12 — 89 69 65 65 13.5 — 90— 66 66 14.5 — 89 — 67 67 16.5 — — — 68 67 17 — 90 72 68 68 19 — 91 7368 69 20 — 91 — 68 70 21 — — — 68 71 22 0 91 77 68 72 Start curing 24 290 81 70 75 24.5 2.5 — — 70 76 25 3 90 — 72 77 26 4 90 — 72 78 27.5 5.5— — 72 79 28 6 82 83 72 78 Good tablet flow, no sticking 32 10 65 73 7269 33 11 — — — 68 35 13 79 74 72 70 37 15 81 76 72 to 25 72 End ofcuring, good tablet flow, no sticking, start cooling 42 — 32 56 25 54 47— 25 50 25 48 good tablet flow, no sticking 52 — 22 36 25 36 56 — 21 2925 30 End cooling, no sticking observed during cool down, good tabletflow ¹determined according to method 2, ²temperature measured at theinlet, ³temperature measured using an IR gun ⁴temperature measured atthe exhaust.

TABLE 16.2.2 Example 16.2 Uncured (n = 60) Coated Tablet DimensionsWeight (mg) 250.8 — Thickness (mm) 4.05 — Breaking strength (Kp) 6.8 — n= 6 Dissolution  1 hr — 22 (% Released)  2 hr — 37 SGF  4 hr — 62  8 hr— 89 12 hr — 97

Example 17

In Example 17, two Oxycodone HCl tablet formulations containing 60 mg ofOxycodone HCl were prepared using high molecular weight polyethyleneoxide. Example 17.1 is the same formulation as presented in Example15.1. The second formulation (Example 17.2) contains 0.1% of butylatedhydroxytoluene. Each tablet formulation was cured at the target exhausttemperature of 72° C. and 75° C. for 15 minutes, followed byfilmcoating, and then an additional curing step at the target exhausttemperature for 30 minutes.

Compositions:

Example 17.1 Example 17.2 mg/unit mg/unit Ingredient Oxycodone HCl  60 60 Polyethylene oxide (MW: approximately 162.75 162.525 4,000,000;Polyox ™ WSR-301) Butylated Hydroxytoluene (BHT)  0  0.225 MagnesiumStearate  2.25  2.25 Total Core Tablet Weight (mg) 225 225 Total Batchsize  5 kg  10 kg Coating Opadry film coating  9  9 Total Tablet Weight(mg) 234 234 Coating Batch Size (kg) 2 kg at 72° C. 6 kg at 72° C. 2 kgat 75° C. 2 kg at 75° C.The processing steps to manufacture tablets were as follows:

-   1. A Patterson Kelly “V’ blender (with I bar)—16 quart was charged    in the following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride (screened through a 20-mesh screen)

Remaining polyethylene oxide WSR 301

-   2. Step 1 materials were blended for 5 minutes with the I bar on.-   3. Magnesium stearate was charged into the “V” blender.-   4. Step 3 materials were blended for 1 minute with the I bar off.-   5. Step 4 blend was charged into a plastic bag (note: two 5 kg    blends were prepared for Example 17.2 to provide 10 kgs of tablet    blend for compression).-   6. Step 5 blend was compressed to target weight on an 8 station    tablet press at 30,000 tph speed using ⅜ inch standard round,    concave (embossed) tooling. Example 17.1 was compressed at a    compression force at 12 kN and Example 17.2 at 6 kN, 12 kN and 18    kN.-   7. Step 6 tablets were loaded into a 15 inch (for 2 kg batch size)    or a 24 inch (for 6 kg batch size) Accela-Coat coating pan.-   8. A temperature probe (wire thermocouple) was placed into the pan    directly above the tablet bed so that the probe tip was near the    cascading bed of tablets.-   9. The pan speed was set at 7 or 10 rpm and the tablet bed was    heated by setting the inlet temperature to achieve an exhaust target    temperature of 72° C. or 75° C. The curing starting point (as    described by method 2) was initiated once the exhaust temperature    achieved target. The inlet temperature was adjusted as necessary to    maintain the target exhaust temperature. The tablets were cured for    15 minutes. The pan speed was maintained at the current rpm. The    temperature profile of the curing processes for Examples 17.1 and    17.2 is presented in Tables 17.1.1 and 17.2.1.-   10. The pan speed was continued at the current rpm. The inlet    temperature was set to 20° or 22° C. and the tablet bed was cooled    until an exhaust temperature of approximately 30° C. was achieved.    NOTE: Magnesium Stearate was not used.-   11. The tablet bed was warmed using an inlet setting of 52°-54° C.    The filmcoating was started once the exhaust temperature achieved    approximately 39°-42° C. and continued until the target weight gain    of 4% was achieved. The pan speed was increased to 15 or 20 rpm    during filmcoating.-   12. After filmcoating was completed, the pan speed was reduced to    the level used during curing. The tablet bed was heated by setting    the inlet temperature to achieve the exhaust target temperature of    72° C. or 75° C. The curing starting point (as described by    method 2) was initiated once the exhaust temperature achieved    target. The inlet temperature was adjusted as necessary to maintain    the target exhaust temperature. The coated tablets were cured for an    additional 30 minutes. The pan speed was maintained at the current    rpm. The temperature profile of the additional curing process for    Examples 17.1 and 17.2 is presented in Tables 17.1.1 and 17.2.1.-   13. The tablets were discharged.

In vitro testing including breaking strength tests was performed asfollows:

Core tablets (uncured), cured tablets and cured/coated tablets weretested in vitro using USP Apparatus 1 (basket with a retaining springplaced at the top of the basket to reduce the propensity of the tabletto stick to the base of the shaft) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) at 37.0° C. Samples were analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC18 3.0×250 mm, 5 μm column, using a mobile phase consistingof a mixture of acetonitrile and potassium phosphate monobasic buffer(pH 3.0) at 230 nm UV detection. Sample time points include 1.0, 2.0,4.0, 6.0, 8.0, 12.0 and 16.0 hours.

Uncured tablets were subjected to a breaking strength test by applying aforce of a maximum of 196 Newton using a Schleuniger 2E/106 apparatus toevaluate tablet resistance to breaking.

Tablet dimensions and dissolution results are presented in Tables

TABLE 17.1.1 Total Curing Temperature Time time Set inlet Actual ProbeExhaust (min.) (min.)¹ (° C.) inlet (° C.)² (° C.)³ (° C.)⁴ CommentsCuring process at 72° C. for Example 17.1 0 — 22 to 80 25.5 28.4 28.5Start heating 10 — 80 80.2 69.6 68.1 19  0 80 to 78 80.0 73.2 72.0 Startof curing 24  5 78 77.9 73.2 73.0 29 10 75 75.0 71.8 72.3 34 15 75 75.072.3 72.0 End of curing, start cooling 50 — 22 22.8 28.2 29.2 Endcooling, ready to coat Apply 4% filmcoat to the tablets, once achievedstart heating 0 — 48 to 80 47.8 45.1 43.1 Start heating for additionalcuring 5 — 80 80.0 68.7 64.9 13  0 80 to 76 80.1 73.2 72.0 Startadditional curing 28 15 75 74.9 72.0 72.4 15 minute additional curing 4330 74 to 22 74.0 71.5 72.1 30 minute additional curing, start cooling 55— 22 24.6 32.2 34 End cooling, discharge Curing process at 75° C. forExample 17.1 0 — 42 to 80 42.1 38.6 38.5 Start heating 18 — 80 to 8380.1 73.0 72.4 21  0 82 81.5 75.1 75.0 Start of curing 26  5 77 76.673.5 74.7 31 10   77.5 77.4 73.8 75.0 36 15 77.5 to 22   77.6 74.1 75.2End of curing, start cooling 53 — 22 23.1 29.5 29.6 End cooling, readyto coat Apply 4% filmcoat to the tablets, once achieved start heating 0— 48 to 83 48.1 44.4 41.5 Start heating for additional curing 12  0 8383.1 75.1 75.0 Start additional curing 27 15 78 78.11 74.4 75.4 15minute additional curing 42 30 76.5 to 22   76.5 73.9 74.9 30 minuteadditional curing, start cooling 56 — 22 23.9 30.3 30.0 End cooling,discharge ¹determined according to method 2, ²temperature measured atthe inlet, ³temperature measured using the temperature probe (wirethermocouple) ⁴temperature measured at the exhaust.

TABLE 17.1.2 Example 17.1 Uncured (n = 25) Tablet Weight (mg) 225 — —Dimensions Thickness (mm) 3.86 — — Breaking strength (N) 75 — — Example17.1 Example 17.1 cured at 72° C. cured at 75° C. 15 min 15 min cureCoated cure Coated n = 3 n = 3 n = 6 n = 3 n = 3 Dissolution 1 hr 27 2726 28 26 (% Released) 2 hr 44 42 41 44 42 SGF 4 hr 68 67 66 69 67 6 hr83 83 84 85 83 8 hr 93 92 93 95 93 12 hr  99 100 100 100 98 16 hr  100102 102 102 99

TABLE 17.2.1 Total Curing Temperature Time time Set inlet Actual ProbeExhaust (min.) (min.)¹ (° C.) inlet (° C.)² (° C.)³ (° C.)⁴ CommentsCuring process at 72° C. for Example 17.2 0 — 80 34.8 33.8 32.1 Pan load6 kg; start heating 10 — 80 76.5 64.5 63.3 20 — 80 80.1 71.1 69.9 27.5 0 80 80.3 73.0 72.0 Start of curing 32.5  5 73.0 73.3 71.0 73.3 37.5 1072.5 72.7 70.2 71.8 42.5 15 73.6 to 22   73.5 70.6 72.1 End of curing,start cooling 61 — 22 22.7 30.1 30 End cooling, ready to coat Apply 4%filmcoat to the tablets, once achieved start heating 0 — 80 to 53 53 —39.5 Start heating for additional curing 15 — 80 79.9 72.3 69.7 18  0 8079.9 74.1 72.0 Start additional curing 33 15 73.5 73.4 70.9 72.3 15minute additional curing 48 30 73.5 73.5 71.4 72.5 30 minute additionalcuring, start cooling 64 — 23.0 23.9 — 30.0 End cooling, dischargeCuring process at 75° C. for Example 17.2 0 — 82 52.9 53   48.4 Pan load2 kg, start heating 12 — 82 82.2 75.4 72.8 16 — 82 to 85 72.6 70.0 69.723.5  0 85 to 82 81.8 76.4 75.0 Start of curing 26.5  3 82 to 80 81.877.2 77.0 32   8.5 78 80.1 76.8 77.1 38.5 15 78 78 75.6 76.1 End ofcuring, start cooling 53 — 20 32.4 30.0 32.1 End cooling, ready to coatApply 4% filmcoat to the tablets, once achieved start heating 0 — 53.5to 83   53.7 — 46.5 Start heating for additional curing —  0 83 83 73.775 Start additional curing — 15 78 77.9 74.3 75.9 15 minute additionalcuring — 23 78 78 75.1 76.3 — 30 78 to 22 78 75.1 76.4 30 minuteadditional curing, start cooling — — 22 23.6 31.0 32.1 End cooling (15minutes of cooling), discharge ¹determined according to method 2,²temperature measured at the inlet, ³temperature measured using thetemperature probe (wire thermocouple) ⁴temperature measured at theexhaust.

TABLE 17.2.2 Example 17.2 Uncured core tablets (n = 5) Compression force(kN) 6 12 18 12 Tablet Weight (mg) 226 227 227 226 Dimensions Thickness(mm) 3.93 3.87 3.86 3.91 Breaking strength 43 71 83 72 (N) Example 17.2cured at Example 17.2 cured at 75° C. 72° C. (6 kg batch) (2 kg batch)15 min cure, Uncured 15 min coated (core) cure Coated Compression force(kN) 6 12 18 12 n = 3 n = 3 n = 3 n = 3 n = 3 n = 3 Dissolution 1 hr 2523 23 26 27 24 (% Released) 2 hr 41 39 37 41 43 40 SGF 4 hr 65 64 59 6466 64 No spring 6 hr 80 81 75 79 81 80 8 hr 90 91 86 88 91 90 12 hr  98100 97 99 101 100 Dissolution 1 hr 26 24 (% Released) 2 hr 42 40 SGF 4hr 66 66 Basket with 6 hr 83 83 spring 8 hr 93 92 12 hr  100 98 16 nr 102 101

Example 18

In Example 18, four different Oxycodone HCl tablet formulationscontaining 80 mg of Oxycodone HCl were prepared using high molecularweight polyethylene oxide at a tablet weight of 250 mg. Two of theformulations (Examples 18.2 and 18.3) contained 0.1% of butylatedhydroxytoluene. One of the formulations (Example 18.4) contained 0.5% ofbutylated hydroxytoluene. Three of the formulations (Examples 18.1,18.2, and 18.4) contained 1% of magnesium stearate. One of theformulations (Example 18.3) contained 0.5% of magnesium stearate.

Compositions:

Example Example Example Example 18.1 18.2 18.3 18.4 mg/unit mg/unitmg/unit mg/unit Ingredient Oxycodone HCl  80  80  80  80 (32%)   (32%)  (32%)   (32%) Polyethylene oxide (MW: 167.5 167.25 166.25 166.25approximately 4,000,000; Polyox ™ WSR-301) (67%) (66.9%) (67.4%) (66.5%)Butylated Hydroxytoluene (BHT) 0  0.25  0.25  1.25  (0.1%)  (0.1%) (0.5%) Magnesium Stearate  2.5 2.5  1.25  2.5  (1%)    (1%)  (0.5%)   (1%) Total Core Tablet Weight (mg) 250 250 250 250 Total Batch size(kg) 5 and 6.3  5  5  5 Coating Opadry film coating n/a  7.5  10 n/aTotal Tablet Weight (mg) n/a 257.5 260 n/a Coating Batch size (kg) n/a 1.975  2.0 n/aThe processing steps to manufacture tablets were as follows:

-   1. A Patterson Kelly “V’ blender (with I bar) 16 quart was charged    in the following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride

BHT (if required)

Remaining polyethylene oxide WSR 301

-   2. Step 1 materials were blended for 10 minutes (Example 18.1, 6.3    kg batch size), 6 minutes (Example 18.2), or 5 minutes (Example    18.1, 5 kg batch size, Example 18.3 and 18.4) with the I bar on.-   3. Magnesium stearate was charged into the “V” blender.-   4. Step 3 materials were blended for 1 minute with the I bar off.-   5. Step 4 blend was charged into a plastic bag.-   6. Step 5 blend was compressed to target weight on an 8 station    tablet press. The compression parameters are presented in Tables    18.1 to 18.4.-   7. Step 6 tablets were loaded into an 18 inch Compu-Lab coating pan    at a pan load of 1.5 kg (Example 18.1 cured at 72° C.), 2.0 kg    (Example 18.1 cured at 75° and 78° C.), 1.975 kg (Example 18.2 cured    at 72° C. and 75° C.), 2.0 kg (Example 18.3), 2.0 kg (Example 18.4    cured at 72° C. and 75° C.).-   8. A temperature probe (wire thermocouple) was placed into the pan    directly above the tablet bed so that the probe tip was near the    moving bed of tablets.-   9. For Examples 18.1 to 18.4, the tablet bed was heated by setting    the inlet temperature to achieve an target exhaust temperature of    72° C., 75° C. or 78° C. The curing starting point (as described by    method 2) was initiated once the exhaust temperature reached the    target exhaust temperature. Once the target exhaust temperature was    achieved, the inlet temperature was adjusted as necessary to    maintain the target exhaust temperature. The tablets were cured for    durations of 15 minutes up to 90 minutes. After curing, the tablet    bed was cooled. The temperature profiles for the curing processes    for Examples 18.1 to 18.4 are presented in Tables 18.1.1 to 18.4.1.-   10. After cooling, the tablet bed was warmed using an inlet setting    of 53° C. (Examples 18.2 and 18.3, for Examples 18.1 and 18.4 film    coating was not performed). The film coating was started once the    exhaust temperature achieved approximately 40° C. and continued    until the target weight gain of 3% (Example 18.2) and 4% (Example    18.3) was achieved.-   11. After film coating was completed (Example 18.2), the tablet bed    was heated by setting the inlet temperature to achieve the exhaust    target temperature (72° C. for one batch and 75° C. for one batch).    The curing starting point (as described by method 2) was initiated    once the exhaust temperature reached the target exhaust temperature.    Once the target exhaust temperature was achieved, the inlet    temperature was adjusted as necessary to maintain the target exhaust    temperature. The film coated tablets were cured for an additional 30    minutes. After the additional curing, the tablet bed was cooled. The    temperature profile for the curing process for Example 18.2 is    presented in Table 18.2.1.-   12. The pan speed was reduced and the inlet temperature was set to    22° C. The system cooled to an exhaust temperature of 30° C.-   13. The tablets were discharged.

In vitro testing including breaking strength tests and stability testswas performed as follows:

Core tablets (uncured), cured tablets, and cured/coated tablets weretested in vitro using USP Apparatus 1 (some testing included basket witha retaining spring placed at the top of the basket to reduce thepropensity of the tablet to stick to the base of the shaft) at 100 rpmin 900 ml simulated gastric fluid without enzymes (SGF) at 37.0° C.Samples were analyzed by reversed-phase high performance liquidchromatography (HPLC) on Waters Atlantis dC18 3.0×250 mm, 5 μm column,using a mobile phase consisting of a mixture of acetonitrile andpotassium phosphate monobasic buffer (pH 3.0) at 230 nm UV detection.Sample time points included 1.0, 2.0, 4.0, 6.0, 8.0, and 12.0 hours.

Uncured tablets were subjected to a breaking strength test by applying aforce of a maximum of 196 Newton using a Schleuniger 2E/106 apparatus toevaluate tablet resistance to breaking.

Example 18.4 tablets (cured at 72° C. and 75° C. respectively) weresubjected to a stability test by storing them in 6 count bottles atdifferent storage conditions (25° C./60% relative humidity or 40° C./75%relative humidity or 50° C.) for a certain period of time andsubsequently testing the tablets in vitro as described above. Sampletime points regarding storage include initial sample (i.e. prior tostorage), two weeks and one month, sample time points regardingdissolution test include 1.0, 2.0, 4.0, 6.0, 8.0 and 12.0 hours.

Tablet dimensions and dissolution results are presented in Tables 18.2.2to 18.4.2.

TABLE 18.1.1 Total Curing Temperature Time time Set inlet Actual ProbeExhaust (min.) (min.)¹ (° C.) inlet (° C.)² (° C.)³ (° C.)⁴ CommentsCuring process at 72° C. for Example 18.1 0 — 23 to 80 24.8 28.4 28.9Pan load 1.5 kg; start heating 10 — 80 76.4 65.5 65.2 15 — 80 79.9 70.870.3 20  0 80 to 78 80.0 72.3 72.0 Start of curing 25  5 78 to 75 76.671.9 72.9 35 15 75 75 71.4 72.0 Sample 40 20 75 75.1 71.7 72.5 50 30 7574.9 72.0 72.7 Sample 60 40 74 73.9 71.4 72.2 65 45 74 74 71.5 72.1Sample 80 60 74 74 71.2 71.8 Sample 95 75 74 73.9 71.7 72.3 Sample 11090 74 to 22 74 71.7 72.3 End of curing, take sample, add 0.3 g ofmagnesium stearate, start cooling 129 — 22 23.1 27.4 26.9 End cooling,no sticking during cool down, discharge Curing process at 75° C. forExample 18.1 0 — 23 to 85 24.1 25.0 24.9 Pan load 2.0 kg, start heating10 — 85 79.6 67.4 66.5 15 — 85 85 73.8 72.3 19  0 85 to 82 85.1 76.275   Start of curing 22  3 82 to 80 80.5 75.3 76.2 29 10 78 78 74.2 75.134 15 78 78.2 73.6 75.1 Sample 49 30 78 77.8 74.5 75.5 Sample 59 40  77.5 77.6  74.66 75.4 64 45   77.5 77.6 74.8 75.4 Sample 79 60   77.577.6 74.6 75.1 Sample 94 75   77.5 77.5 74.5 75.1 Sample, minor sticking109 90   77.5 77.6 75.0 75.6 End of curing, take sample, start cooling116 — 22 30.6 42.6 46.7 Minor sticking at support arms 122 — 22 25 —33.5 End cooling Curing process at 78° C. for Example 18.1 0 — 82 3537.6 35.9 Pan load 2 kg, start heating 7 — 85 84.9 71.3 69.8 14 — 8584.9 75.9 75.0 17.5  0 85 to 83 85.1 77.4 78.0 Start of curing 22.5  583 83.2 77.5 78.6 32.5 15 82 81.9 76.9 78.4 Sample 47.5 30 81 80.9 77.478.3 Sample 57.5 40   80.5 80.6 77.5 78.1 62.5 45   80.5 80.7 77.4 78.2Sample 69.5 52   80.5 80.4 77.5 78.2 Minor sticking 77.5 60   80.5 80.677.6 78.3 Sample, sticking 87.5 70 — — — — Add 0.3 g of magnesiumstearate 92.5 75   80.0 79.8 77.1 78.1 Sample, sticking continued, briefimprovement of tablet flow with magnesium stearate addition 107.5 90  80.0 79.9 77.5 78.0 Sample, start cooling ¹determined according tomethod 2, ²temperature measured at the inlet, ³temperature measuredusing the temperature probe (wire thermocouple) ⁴temperature measured atthe exhaust.

TABLE 18.2 Example 18.1 (6.3 kg batch) Uncured core tablets n = 12Compression force (kN) 15 Tablet Weight (mg) 250 Dimensions Thickness(mm) 4.08 Breaking strength (N) 87 Example 18.1 cured at 72° C. uncured15 min cure 60 min cure n = 3 n = 3 n = 2 Dissolution  1 hr 25 26 25 (%Released)  2 hr 40 40 40 SGF  4 hr 66 64 62 No spring  8 hr 95 89 91 12hr 102 97 92 Example 18.1 (5.0 kg batch) Uncured core tablets n = 25Compression force (kN) 15 Tablet Weight (mg) 253 Dimensions Thickness(mm) 4.13 Breaking strength (N) 92 Example 18.1 cured at 75° C. Example18.1 15 min 60 min cured at 78° C. uncured cure cure 30 min cure n = 3 n= 3 n = 3 n = 3 Dissolution  1 hr 26 26 26 26 (% Released)  2 hr 40 4142 41 SGF  4 hr 63 67 68 66 No spring  8 hr 90 94 94 93 12 hr 101 101100 101

TABLE 18.2.1 Total Curing Temperature Time time Set inlet Actual ProbeExhaust (min.) (min.)¹ (° C.) inlet (° C.)² (° C.)³ (° C.)⁴ CommentsCuring process at 72° C. for Example 18.2 0 — 42 to 80 41.9 37.4 37.8Pan load 1.975 kg, start heating 10 — 80 80.0 68.0 68.6 18  0 80 80.171.6 72.0 Start of curing 28 10 75 74.5 70.7 72.4 33 15 75 to 22 75.071.1 72.3 End of curing, start cooling 47.5 — 22 22.5 30.4 30.0 Endcooling, sample, ready to coat Apply 3% filmcoat to the tablets, onceachieved start heating 0 — 50 to 80 50 48.0 43.0 Start heating foradditional curing 12  0 80 to 77 80.0 72.1 72.0 Start additional curing27 15 75 74.9 71.0 72.4 Sample 15 minute additional curing 42 30 74 to22 73.9 70.7 72.1 Sample, 30 minute additional curing, start cooling 61— 22 — — 30 End cooling, discharge, sample Curing process at 75° C. forExample 18.2 0 — 42 to 82 41.8 39.7 40.1 Pan load 1.975 kg, startheating 13 — 82 82 73.0 72.2 18  0 82 to 80 81.9 75.2 75.0 Start ofcuring 33 15 78 to 22 77.8 74.2 75.4 End of curing, start cooling, nosticking 49 — 22 22.5 28.8 29.5 End cooling, sample, ready to coat Apply3% filmcoat to the tablets, once achieved start heating 0 — 48 to 8348.0 44.5 41.5 Start heating for additional curing 13  0 83 83.3 75.675.4 Start additional curing 28 15 78 78.0 74.6 75.4 Sample 15 minuteadditional curing 44.5   31.5 77.5 to 22   77.4 74.4 75.4 Sample 30minute additional curing, start cooling 58.5 — 22 24.2 — 30 End cooling,discharge, sample ¹determined according to method 2, ²temperaturemeasured at the inlet, ³temperature measured using the temperature probe(wire thermocouple) ⁴temperature measured at the exhaust.

TABLE 18.2.2 Example 18.2 Uncured core tablets n = 10 n = 10 n = 10Tooling size, round ⅜ ⅜ 13/32 (in) Compression force 8 15 15 (kN) TabletWeight (mg) 253 253 252 Dimensions Thickness (mm) 4.24 4.21 3.77Breaking strength 50 68 55 (N) Example 18.2 cured at 72° C. Compressionforce (kN) 8 15 15 15 min cure, 15 min cure, 15 min cure, coated coatedcoated n = 3 n = 6 n = 3 n = 6 n = 3 No With No With No With DissolutionBasket* spring spring spring spring spring spring Dissolution¹ 1 hr 22(4.9) 23 (6.5) 22 (4.8) 24 (5.6) 23 (2.2) (% Released) 2 hr 36 (6.1) 38(5.4) 36 (6.7) 39 (4.4) 37 (3.9) SGF 4 hr 58 (5.8) 63 (2.3) 58 (7.0) 63(2.3) 59 (5.2) 6 hr 75 (4.9) 80 (1.2) 75 (4.9) 80 (1.6) 76 (4.2) 8 hr 87(4.1) 90 (1.2) 88 (3.1) 90 (1.8) 88 (3.2) 12 hr  96 (1.9) 99 (0.8) 97(1.2) 98 (1.6) 97 (1.1) 16 hr  — 100 (1.4)  — 101 (2.8)  — *Some testingincluded the use of a retaining spring placed at the top of the basketto reduce the propensity of the tablet to stick to the base of theshaft; ¹the values in parantheses indicate relative standard deviation.

TABLE 18.3.1 Curing process at 72° C. for Example 18.3 Total CuringTemperature Time time Set inlet Actual Probe Exhaust (min.) (min.)¹ (°C.) inlet (° C.)² (° C.)³ (° C.)⁴ Comments 0 — 22 to 80 25.1 29.4 30.1Pan load 2.0 kg, start heating 10 — 80 80.2 68.3 68.0 19 0 80 80.0 71.872.0 Start of curing 24 5 76 75.7 71.2 72.5 29 10 76 to 75 76.0 71.372.7 34 15 75 to 22 74.9 70.7 72.2 End of curing, start cooling 49 — 2222.9 29.1 29.7 End cooling ¹determined according to method 2,²temperature measured at the inlet, ³temperature measured using thetemperature probe (wire thermocouple) ⁴temperature measured at theexhaust.

TABLE 18.3.2 Example 18.3 Uncured core tablets Tooling Round ⅜ inch Oval0.600 × 0.270 inch Compression force (kN) 15 10-11 n = 5 n = 5 TabletWeight (mg) 250 250 Dimensions Thickness (mm) 4.20 3.80-3.84 Breakingstrength (N) 83-110 71-76 Example 18.3 cured at 72° C. 15 min cure,coated 15 min cure, coated Round 3/8 inch Oval 0.600 × 0.270 inch n = 6n = 6 n = 6 Dissolution Basket * No spring With spring No springDissolution¹  1 hr 23 (7.0) 23 (4.9) 24 (7.2) (% Released)  2 hr 37(6.2) 38 (3.4) 40 (6.0) SGF  4 hr 59 (4.6) 61 (1.9) 64 (5.0)  6 hr 75(3.5) 79 (1.5) 81 (2.8)  8 hr 87 (2.7) 89 (2.1) 91 (2.0) 12 hr 98 (2.6)98 (2.6) 98 (1.6) * Some testing included the use of a retaining springplaced at the top of the basket to reduce the propensity of the tabletto stick to the base of the shaft. ¹the values in parentheses indicaterelative standard deviation.

TABLE 18.4.1 Total Curing Temperature Time time Set inlet Actual ProbeExhaust (min.) (min.)¹ (° C.) inlet (° C.)² (° C.)³ (° C.)⁴ CommentsCuring process at 72° C. for Example 18.4 0 — 82 35.6 37.3 36.3 Pan load2.0 kg; start heating 8 — 82 82 69.8 68.8 13.5 0 82 82 72.6 72.0 Startof curing 18.5 5 80 to 79 79.6 72.0 73.5 23.5 10 76 75.9 71.4 73.0 28.515 75 75 70.9 72.4 Sample 38.5 25 75 74.9 70.9 72.5 43.5 30 75 75 71.172.6 Sample 51.5 38 75 75.1 71.4 72.7 58.5 45 75 75 71.4 72.8 Sample68.5 55 75 75.2 71.6 73.0 73.5 60 75 75 71.5 73 End of curing, sample,start cooling 78.5 — 23 37.4 48 52.2 Continue cooling Curing process at75° C. for Example 18.4 0 — 85 26.1 31.0 29.1 Pan load 2.0 kg, startheating 5 — 82 73.8 61.9 61.1 11 — 82 79.9 69.3 68.3 17.5 0 85 85 76.275 Start of curing 27.5 10 78 77.8 74.4 76.1 32.5 15 78 77.9 74.5 75.9Sample 39.5 22 77.55 77.4 74.1 75.6 47.5 30 77.5 77.4 74.2 75.6 Sample55.5 38 77 76.9 74.0 75.4 62.5 45 77 77 73.9 75.3 Sample 69.5 52 77 77.273.8 75.3 77.5 60 77 77.0 73.7 75.3 End of curing, sample, start cooling¹determined according to method 2, ²temperature measured at the inlet,³temperature measured using the temperature probe (wire thermocouple)⁴temperature measured at the exhaust.

TABLE 18.4.2 Example 18.4 Uncured core tablets n = 25 Compression force(kN) 15 Tablet Weight (mg) 254  Dimensions Thickness (mm)    4.15Breaking strength (N) 85 Example 18.4 Example 18.4 cured at 72° C. curedat 75° C. 15 min 60 min 15 min 60 min uncured cure cure cure cure n = 3n = 3 n = 3 n = 3 n = 3 Dissolution 1 hr 26 26 26 26 25 (% Released) 2hr 41 41 41 42 40 SGF 4 hr 63 64 65 65 64 No spring 8 hr 89 89 94 91 8912 hr  98 99 100  100  99 Example 18.4, 2 week stability 15 min cure at72° C. initial 25/60¹ 40/75¹ 50° C. n = 3 n = 4 n = 4 n = 4 Dissolution1 hr 26 26 26 27 (% Released) 2 hr 41 40 41 42 SGF 4 hr 64 62 63 65 Nospring 6 hr — — — — 8 hr 89 88 90 92 12 hr  99 99 99 102  Example 18.4,2 week stability 15 min cure at 75° C. initial 25/60¹ 40/75¹ 50° C. n =3 n = 4 n = 4 n = 4 Dissolution 1 hr 26 25 26 25 (% Released) 2 hr 42 3941 40 SGF 4 hr 65 60 64 63 No spring 6 hr — — — — 8 hr 91 84 90 91 12hr  100  95 99 99 Example 18.4 1 month stability 15 min cure at 72° C.initial 25/60¹ 40/75¹ 50° C. n = 3 n = 4 n = 4 n = 3 Dissolution 1 hr 2626 26 26 (% Released) 2 hr 41 41 40 41 SGF 4 hr 64 63 63 66 No spring 6hr — 79 79 83 8 hr 89 89 91 93 12 hr  99 98 99 101  ¹storage conditions,i.e. 25° C./60% RH or 40° C./75% RH

Example 19

In Example 19, two different Oxycodone HCl tablet formulationscontaining 80 mg of Oxycodone HCl were prepared using high molecularweight polyethylene oxide at a tablet weight of 250 mg. One of theformulations (Example 19.1) contained Polyethylene oxide N60K and oneformulation (Example 19.2) contained Polyethylene oxide N12K.

Compositions:

Example 19.1 Example 19.2 Ingredient mg/unit mg/unit Oxycodone HCl 80 80  (32%)   (32%) Polyethylene oxide (MW: approximately 168.75 02,000,000; Polyox ® WSR- N60K) (67.5%) Polyethylene oxide (MW:approximately 0 168.75 1,000,000; Polyox ™ WSR- N12K) (67.5%) MagnesiumStearate 1.25 1.25  (0.5%)  (0.5%) Total Core Tablet Weight (mg) 250 250Total Batch size (kg) 2.0 2.0 Coating mg/unit mg/unit Opadry filmcoating 10 10 Total Tablet Weight (mg) 260 260 Coating Batch size (kg)1.4 1.4The processing steps to manufacture tablets were as follows:

-   1. A Patterson Kelly “V’ blender (with I bar)—8 quart was charged in    the following order:    -   Approximately ½ of the polyethylene oxide    -   Oxycodone hydrochloride    -   Remaining polyethylene oxide    -   Note: the polyethylene oxide was screened through a 20-mesh        screen, retain material was not used.-   2. Step 1 materials were blended for 5 minutes with the I bar on.-   3. Magnesium stearate was charged into the “V” blender.-   4. Step 3 materials were blended for 1 minute with the I bar off.-   5. Step 4 blend was charged into a plastic bag.-   6. Step 5 blend was compressed to target weight on an 8 station    tablet press at 30,000 tph speed using ⅜ inch standard round,    concave (embossed) tooling. The compression parameters are presented    in Tables 19.1 and 19.2.-   7. Step 6 tablets were loaded into an 18 inch Compu-Lab coating pan.-   8. A temperature probe (wire thermocouple) was placed into the pan    directly above the tablet bed so that the probe tip was near the    moving bed of tablets.-   9. The tablet bed was heated by setting the inlet temperature to    achieve an exhaust target temperature of 72° C. The curing starting    point (as described by method 2) was initiated once the exhaust    temperature reached the target temperature. Once the target exhaust    temperature was achieved, the inlet temperature was adjusted as    necessary to maintain the target exhaust temperature. The tablets    were cured for 15 minutes. After curing, the inlet temperature was    set to 22° C. and the tablet bed was cooled. The temperature    profiles for the curing processes for Examples 19.1 and 19.2 are    presented in Tables 19.1.1 and 19.2.1.-   10. After cooling, the tablet bed was warmed using an inlet setting    of 53° C. The film coating was started once the exhaust temperature    achieved approximately 41° C. and continued until the target weight    gain of 4% was achieved.-   11. After film coating was completed, the tablet bed was cooled by    setting the inlet temperature to 22° C. The tablet bed was cooled to    an exhaust temperature of 30° C. or less was achieved.-   12. The tablets were discharged.

In vitro testing including breaking strength tests was performed asfollows:

Core tablets (uncured), cured tablets, and cured/coated tablets weretested in vitro using USP Apparatus 1 (basket with a retaining springplaced at the top of the basket to reduce the propensity of the tabletto stick to the base of the shaft) at 100 rpm in 900 ml simulatedgastric fluid without enzymes (SGF) at 37.0° C. Samples were analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC18 3.0×250 mm, 5 μm column, using a mobile phase consistingof a mixture of acetonitrile and potassium phosphate monobasic buffer(pH 3.0) at 230 nm UV detection. Sample time points included 1.0, 2.0,4.0, 6.0, 8.0, 12.0 and 16.0 hours.

Uncured tablets were subjected to a breaking strength test by applying aforce of a maximum of 196 Newton using a Schleuniger 2E/106 apparatus toevaluate tablet resistance to breaking.

Tablet dimensions and dissolution results are presented in Tables 19.1.2and 19.2.2.

TABLE 19.1.1 Example 19.1 (PEO N60K) Total Curing Temperature Time timeSet inlet Actual Probe Exhaust (min.) (min.)¹ (° C.) inlet (° C.)² (°C.)³ (° C.)⁴ Comments 0 — 22 to 80 25.3 26.4 26.9 Pan load 1.4 kg; startheating 21  0 80 79.9 70.0* 72.0 Start of curing 31 10   75.5 75.5 69.1*72.2 Good tablet flow, no sticking 36 15 75.5 to 22 75.4 69.5* 72.4 Endof curing, start cooling 50 — 22 22.6 27.5 30.0 End of cooling, sample¹determined according to method 2, ²temperature measured at the inlet,³temperature measured using the temperature probe (wire thermocouple)⁴temperature measured at the exhaust; *Low temperature values comparedto the exhaust temperature. Changed the battery prior to processingExample 19.2.

TABLE 19.1.2 Example 19.1 (PEO N60K) Uncured core tablets n = 15Compression 15 force (kN) Tablet Weight (mg) 252 Dimensions Thickness(mm) 4.12 Breaking 112 strength (N) Example 19.1 cured at 72° C. uncured15 min cure Cured/coated n = 3 n = 3 n = 6 Dissolution  1 hr 25 (2.3) 25(2.1) 25 (3.7) (% Released)  2 hr 40 (1.8) 40 (1.3) 40 (3.8) SGF  4 hr67 (0.7) 66 (1.5) 65 (1.4) Basket with  6 hr 85 (1.0) 86 (3.9) 84 (1.0)spring  8 hr 97 (0.8) 98 (1.8) 95 (0.7) 12 hr 101 (1.2)  103 (1.2)  102(0.8)  16 hr 102 (0.7)  103 (2.0)  103 (1.1) 

TABLE 19.2.1 Example 19.2 (PEO N12K) Total Curing Temperature Time timeSet inlet Actual Probe Exhaust (min.) (min.)¹ (° C.) inlet (° C.)² (°C.)³ (° C.)⁴ Comments 0 — 22 to 80 27.0 31.4 30.9 Pan load 1.4 kg; startheating 19.5  0 80 80.1 71.5 72.0 Start of curing 24.5  5 77 76.7 71.072.8 29.5 10 75 75.0 70.3 72.0 Good tablet flow, no sticking 34.5 15 75to 22 75.1 70.4 72.0 End of curing, start cooling 49 — 22 22.4 30.0 30.0End of cooling, sample ¹determined according to method 2, ²temperaturemeasured at the inlet, ³temperature measured using the temperature probe(wire thermocouple) ⁴temperature measured at the exhaust.

TABLE 19.2.2 Example 19.1 (PEO N12K) Uncured core tablets n = 15Compression 15 force (kN) Tablet Weight (mg) 257 Dimensions Thickness(mm) 4.17 Breaking 107 strength (N) Example 19.2 cured at 72° C. uncured15 min cure Cured/coated n = 3 n = 3 n = 6 Dissolution  1 hr 277 (7.6) 25 (1.0)  26 (4.0) (% Released)  2 hr  44 (4.9)  42 (0.6)  43 (3.7) SGF 4 hr  72 (2.5)  70 (0.6)  71 (1.8) Basket with  6 hr  92 (1.1)  92(0.6)  91 (1.2) spring  8 hr 102 (0.9) 101 (1.1) 100 (1.4) 12 hr 102(1.1) 101 (0.9) 101 (1.3) 16 hr 103 (0.3) 103 (1.3) 102 (1.1)

Example 20 Indentation Test

In Example 20, tablets corresponding to Examples 13.1 to 13.5, 14.1 to14.5, 16.1, 16.2, 17.1 and 18.2 were subjected to an indentation testwith a Texture Analyzer to quantify the tablet strength.

The indentation tests were performed with a TA-XT2 Texture Analyzer(Texture Technologies Corp., 18 Fairview Road, Scarsdale, N.Y. 10583)equipped with a TA-8A ⅛ inch diameter stainless steel ball probe. Theprobe height was calibrated to 6 mm above a stainless stand withslightly concaved surface. The tablets were placed on top of thestainless stand and aligned directly under the probe. Each type oftablets was tested at least once. Single measurement values arereported. Testing performed on the same type of tablet produced similarresults unless the tablet and the probe were misaligned. In such anevent, the data would be rejected upon confirmation by visualexamination of the tested tablet.

The indentation tests were run with the following parameters:

pre-test speed 0.5 mm/s, test speed 0.5 mm/s, automatic trigger force 10grams, post-test speed 1.0 mm/s, test distance 3.0 mm.

The results are presented in Tables 20.1 to 20.3 and in FIGS. 20 to 33.

TABLE 20.1 Cracking force, “penetration depth to crack” distance andwork values Indentation Test Results Cracking Maximum Distance WorkForce (N) Force (N) ⁶ (mm) ⁷ (J) ⁸ Example 13.1¹ — 189 3.00 0.284Example 13.2¹ — 188 3.00 0.282 Example 13.3¹ 191 — 2.91 0.278 Example13.4¹ 132 — 1.81 0.119 Example 13.5¹ 167 — 1.82 0.152 Example 17.1² >250⁵   — >2.0 >0.250 Example 18.2² 194 — 1.80 0.175 Example 14.1³ 213— 2.52 0.268 Example 14.2³ 196 — 2.27 0.222 Example 14.3³ 161 — 1.900.153 Example 14.4³ 137 — 1.51 0.103 Example 14.5³ 134 — 1.39 0.093Example 16.1⁴ 227 — 2.23 0.253 Example 16.2⁴ 224 — 2.17 0.243¹indentation test performed with tablets cured for 30 min and uncoated(curing time determined according to method 4, curing started when theprobe temperature reached 70° C., see Example 13). ²indentation testperformed with tablets cured at 72° C. for 15 minutes and coated (curingtime determined according to method 2, curing started when the exhaustair temperature reached 72° C., see Examples 17 and 18), ³indentationtest performed with tablets cured for 1 hour and coated (curing timedetermined according to method 1, curing started when the inlet airtemperature reached 75° C., see Example 14), ⁴indentation test performedwith tablets cured for 15 minutes and coated (curing time determinedaccording to method 2, curing started when the exhaust air temperaturereached 72° C., see Example 16), ⁵The peak force exceeded the detectionlimit, ⁶ In the indentation tests where the tablets did not crack underthe test conditions given above, the maximum force at penetration depthof 3.0 mm is given instead of a cracking force; ⁷ “penetration depth tocrack” distance ⁸ approximated value, calculated using the equation:Work ≈ ½ · Force [N] × Distance [m].

TABLE 20.2 Selective force values at incremental distance change of 0.1mm Distance Force (N) (mm) Ex. 13.1 Ex. 13.2 Ex. 13.3 Ex. 13.4 Ex. 13.5Ex. 17.1 Ex. 18.2 0.0 0.18 0.18 0.15 0.17 0.24 0.14 0.35 0.1 3.54 4.863.67 4.38 5.35 6.12 6.88 0.2 8.76 10.56 9.95 10.29 12.37 15.13 15.51 0.315.49 16.97 16.85 17.62 22.22 25.57 25.33 0.4 22.85 24.19 23.81 25.4432.98 35.86 35.21 0.5 30.43 31.59 30.81 33.42 43.85 46.10 45.25 0.637.80 38.82 38.42 41.49 55.41 56.87 55.60 0.7 45.61 46.10 46.61 49.7367.02 67.69 66.85 0.8 53.30 53.08 54.53 58.37 78.43 78.71 78.24 0.960.67 60.25 62.38 67.00 89.60 90.74 89.60 1.0 68.02 67.55 70.89 75.45100.38 103.18 101.69 1.1 75.29 74.67 80.12 83.75 110.46 116.10 114.501.2 82.81 81.40 89.03 91.14 119.87 129.90 127.13 1.3 90.04 88.23 97.4998.35 129.16 144.28 139.46 1.4 96.85 95.21 105.89 105.88 138.29 158.94151.41 1.5 103.92 101.84 114.37 112.94 146.76 173.41 162.88 1.6 111.30108.30 122.31 119.59 154.61 188.13 173.95 1.7 118.27 115.16 129.99125.85 161.87 202.39 184.52 1.8 125.02 121.81 136.94 131.63 167.65216.08 193.31 1.9 131.71 128.37 143.45 137.30 165.05 229.06 190.80 2.0138.09 134.64 149.56 142.86 163.03 241.23 191.16 2.1 144.38 140.46155.52 148.05 165.82 250.17¹ 192.11 2.2 150.54 146.46 160.93 153.34168.86 — 191.84 2.3 156.18 152.31 166.39 158.55 171.13 — 189.31 2.4161.57 157.73 171.41 163.52 172.21 — 185.17 2.5 166.80 163.24 176.29168.34 171.66 — 179.55 2.6 171.67 168.53 180.67 172.34 169.90 — 173.092.7 176.24 173.45 184.52 175.57 167.51 — 166.68 2.8 180.39 178.37 187.79177.84 164.67 — 158.70 2.9 184.61 183.24 190.54 180.35 161.12 — 148.393.0 188.65 187.97 192.92 182.88 156.21 — 137.65 ¹Force value at adistance of 2.0825 mm

TABLE 20.3 Selective force values at incremental distance change of 0.1mm Distance Force (N) (mm) Ex. 14.1 Ex. 14.2 Ex. 14.3 Ex. 14.4 Ex. 14.5Ex. 16.1 Ex. 16.2 0.0 0.33 0.27 0.33 0.31 0.41 0.27 0.26 0.1 6.06 6.036.55 6.61 5.78 6.22 7.25 0.2 13.81 13.05 13.65 15.53 13.51 13.88 15.520.3 22.48 21.42 21.55 24.82 21.87 23.31 25.11 0.4 31.41 29.68 29.5134.09 31.12 33.72 35.29 0.5 40.00 37.79 37.99 43.44 41.26 43.82 45.310.6 48.85 46.69 47.69 52.78 52.22 54.19 55.47 0.7 57.85 55.26 57.1962.09 63.53 64.60 66.58 0.8 66.76 64.45 66.87 71.64 74.72 75.69 78.370.9 75.69 73.68 76.43 81.47 85.73 87.70 90.38 1.0 84.63 83.33 86.3191.14 96.72 99.88 103.07 1.1 94.04 92.81 95.86 100.28 107.27 112.14116.67 1.2 103.45 101.93 105.14 109.77 118.11 124.54 130.10 1.3 112.69111.76 115.04 119.97 128.22 137.12 143.13 1.4 122.63 122.04 125.05129.55 133.77 149.34 155.78 1.5 132.50 132.04 134.14 137.20 134.95161.51 168.25 1.6 141.98 141.82 142.58 135.04 139.81 173.01 180.44 1.7151.21 150.82 150.69 139.12 144.84 184.28 192.28 1.8 160.27 159.44157.82 143.60 148.83 194.58 203.45 1.9 169.02 168.09 161.72 146.81151.39 204.27 212.71 2.0 177.84 176.40 162.87 148.59 152.52 213.25218.71 2.1 186.18 184.67 165.88 149.32 152.56 221.06 223.17 2.2 194.39192.38 169.78 149.19 151.29 226.97 224.84 2.3 202.16 196.66 173.59148.16 147.83 219.64 226.60 2.4 208.46 199.43 176.38 146.05 141.54210.57 228.33 2.5 212.94 202.98 178.44 142.81 134.06 203.85 228.97 2.6213.83 206.77 179.87 137.70 124.24 197.33 228.49 2.7 216.58 209.46181.13 131.34 109.53 189.49 227.40 2.8 219.71 211.32 182.02 123.72 88.60181.26 225.10 2.9 222.51 211.01 181.70 114.09 20.86 174.45 222.87 3.0224.59 208.85 179.91 102.93 0.16 168.70 220.36

Example 21 Indentation Test

In Example 21, tablets corresponding to Examples 16.1 (60 mg OxycodoneHCl) and 16.2 (80 mg oxycodone HCL) and commercial Oxycontin™ 60 mg andOxycontin™ 80 mg tablets were subjected to an indentation test with aTexture Analyzer to quantify the tablet strength.

The indentation tests were performed as described in Example 20.

The results are presented in Table 21 and in FIGS. 34 and 35.

TABLE 21 Selective force values at incremental distance change of 0.1 mmDistance Force (N) (mm) Ex. 16.1 Oxycontin ™ 60 mg Ex. 16.2 Oxycontin ™80 mg 0.0 0.27 0.42 0.26 0.42 0.1 6.22 14.14 7.25 14.21 0.2 13.88 30.3915.52 29.75 0.3 23.31 46.53 25.11 44.30 0.4 33.72 61.94 35.29 59.46 0.543.82 78.14 45.31 75.33 0.6 54.19 13.58 55.47 91.91 0.7 64.60 0.30 66.58108.71 0.8 75.69 0.09 78.37 1.48 0.9 87.70 0.00 90.38 1.52 1.0 99.880.01 103.07 1.17 1.1 112.14 0.01 116.67 1.31 1.2 124.54 0.00 130.10 3.611.3 137.12 0.01 143.13 7.85 1.4 149.34 0.00 155.78 3.49 1.5 161.51 0.00168.25 0.15 1.6 173.01 0.00 180.44 0.85 1.7 184.28 0.00 192.28 1.46 1.8194.58 0.00 203.45 1.12 1.9 204.27 0.00 212.71 0.81 2.0 213.25 0.02218.71 0.52 2.1 221.06 −0.01 223.17 0.14 2.2 226.97 −0.01 224.84 0.132.3 219.64 −0.01 226.60 0.10 2.4 210.57 0.01 228.33 0.09 2.5 203.85 0.00228.97 0.08 2.6 197.33 0.00 228.49 0.08 2.7 189.49 −0.01 227.40 0.07 2.8181.26 0.00 225.10 0.08 2.9 174.45 0.00 222.87 0.07 3.0 168.70 0.00220.36 0.08

Comparative Example 22

In Comparative Example 22, five different 150 mg tablets (Examples 22.1to 22.5) including 10, 15, 20, 30 and 40 mg of oxycodone HCl wereprepared using the compositions as described in Example 13, and amendingthe manufacturing process of Example 13 insofar that the tablets weresubjected to a molding step instead of a curing step.

Compositions:

Example Example Example Example Example 22.1 22.2 22.3 22.4 22.5Ingredient mg/unit mg/unit mg/unit mg/unit mg/unit Oxycodone HCl 10 1520 30 40 Polyethylene oxide 138.5 133.5 128.5 118.5 108.5 (MW:approximately 4,000,000; Polyox ™ WSR-301) Magnesium Stearate 1.5 1.51.5 1.5 1.5 Total Core Tablet 150 150 150 150 150 Weight (mg) TotalBatch size 10 kg 10 kg 10 kg 10 kg 10 kgThe processing steps to manufacture tablets were as follows:

-   1. A Patterson Kelly “V’ blender (with I bar)—16 quart was charged    in the following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Remaining polyethylene oxide WSR 301

-   2. Step 1 materials were blended for 5 minutes with the I bar on.-   3. Magnesium stearate was charged into the “V” blender.-   4. Step 3 materials were blended for 1 minute with the I bar off.-   5. Step 4 blend was charged into a plastic bag.-   6. Step 5 blend was compressed to target weight on an 8 station    tablet press at 35,000 tph speed using 9/32 inch standard round,    concave (embossed) tooling.-   7. Step 6 tablets were molded with a temperature controlled Specac    press. The compressed tablets from step 6 were placed between two    heated plates which were preheated to 120° C. and then compressed at    a pressured setting of 1000 kg and held for 3 minutes. The molten    tablets were cooled to room temperature prior to density    measurement.

The density measurement was performed as follows:

The density of tablets before and after the molding step was determinedby Archimedes principle, using a Top-loading Mettler Toledo balanceModel #AB 135-S/FACT, Serial #1127430072 and a density determination kit33360, according to the following procedure:

-   1. Set-up the Mettler Toledo balance with the Density Determination    Kit.-   2. Fill an appropriately sized beaker (200 ml) with hexane.-   3. Weigh the tablet in air and record the weight as Weight A.-   4. Transfer the same tablet onto the lower coil within the beaker    filled with hexane.-   5. Determine the weight of the tablet in hexane and record the    weight as Weight B.-   6. Perform the density calculation according to the equation

${\rho = {\frac{A}{A - B} \cdot \rho_{0}}},$

wherein

-   -   ρ: Density of the tablet    -   A: Weight of the tablet in air    -   B: Weight of the tablet when immersed in the liquid    -   ρ₀: Density of the liquid at a given temperature (density of        hexane at 20° C.=0.660 g/ml (Merck Index)

-   7. Record the density.    The reported density values are mean values of 3 tablets and all    refer to uncoated tablets.

The results are presented in Table 22.1.

TABLE 22.1 Density (g/cm³)¹ Density change after Unmolded tablet² Moldedtablet molding (%)³ Example 22.1 1.172 1.213 +3.498 Example 22.2 1.1741.213 +3.322 Example 22.3 1.179 1.222 +3.647 Example 22.4 1.182 1.231+4.146 Example 22.5 1.222 1.237 +1.227 ¹The density value is a meanvalue of 3 tablets measured; ²The density of the “unmolded tablet”corresponds to the density of the “uncured tablet” of Examples 13.1 to13.5; ³The density change after molding corresponds to the observeddensity change in % of the molded tablets in comparison to the unmoldedtablets.

Example 23

In Example 23, 154.5 mg tablets including 30 mg Hydromorphone HCl wereprepared using high molecular weight polyethylene oxide.

Composition:

Ingredient mg/unit g/batch Hydromorphone HCl 30 1000 Polyethylene oxide(MW: approximately 119.25 3975 4,000,000: Polyox ™ WSR- 301) MagnesiumStearate 0.75 25 Total Core Tablet Weight (mg) 150 Total Batch size 10kg (2 × 5 kg) Coating mg/unit Opadry film coating 4.5 Total TabletWeight (mg) 154.5 Coating Batch Size (kg) 8.835 kg

The processing steps to manufacture tablets were as follows:

-   1. A PK V-blender (with I-bar)—16 quart was charged in the following    order:

Approximately half of the Polyethylene Oxide 301

Hydromorphone HCl

Remaining Polyethylene Oxide 301

-   2. Step 1 materials were blended for 5 minutes with the intensifier    bar ON.-   3. Magnesium stearate was charged in the PK V-blender.-   4. Step 3 materials were blended for 1 minute with the intensifier    bar OFF.-   5. Step 4 blend was charged into a plastic bag (Note: two 5 kg    blends were produced to provide 10 kgs available for compression).-   6. Step 5 blend was compressed to target weight on an 8 station    rotary tablet press using 9/32 inch standard round, concave    (embossed) tooling at 35,000 to 40,800 tph speed using 5-8 kN    compression force.-   7. Step 6 tablets were loaded into a 24 inch Compu-Lab coating pan    at a pan load of 9.068 kg.-   8. The pan speed was set to 10 rpm and the tablet bed was heated by    setting the inlet air temperature to achieve an exhaust temperature    of approximately 72° C. The curing starting point (as described by    method 2) was initiated once the exhaust temperature achieved 72° C.    The tablets were cured at the target exhaust temperature for 1 hour.    Tablet samples were taken after 30 minutes of curing.-   9. After 1 hour of curing at the target exhaust temperature of 72°    C., the inlet temperature was set to 90° C. to increase the exhaust    temperature (the bed temperature).-   10. After 10 minutes of increased heating, the exhaust temperature    reached 82° C. The tablet continued to maintain good flow/bed    movement. No sticking was observed.-   11. The inlet temperature was set to 22° C. to initiate cooling.    During the cool down period (to an exhaust temperature of 42° C.),    no sticking or agglomerating of tablets was observed.-   12. Step 11 tablets were loaded into a 24 inch Compu-Lab coating pan    at a pan load of 8.835 kg.-   13. The tablet bed was warmed by setting the inlet air temperature    at 55° C. The film coating was started once the exhaust temperature    approached 42° C. and continued until the target weight gain of 3%    was achieved.-   14. Film coating was conducted at a spray rate of 40-45 g/min,    airflow target at 350 cfm, and pan speed initiated at 10 rpm and    increased to 15 rpm. After coating was completed the pan speed was    set to 3.5 rpm and the tablets were allowed to cool.-   15. The tablets were discharged.

In vitro testing including dissolution, assay and content uniformitytest was performed as follows:

Tablets cured for 30 minutes (uncoated) were tested in vitro using USPApparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37.0° C. Samples were analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC18 3.0×250 mm, 5 μm column, using a mobile phase consistingof a mixture of acetonitrile and potassium phosphate monobasic buffer(pH 3.0) at 220 nm UV detection. Sample time points include 1.0, 2.0,4.0, 8.0 and 12.0 hours.

Tablets cured for 30 minutes (uncoated) were subjected to the assaytest. Oxycodone hydrochloride was extracted from two sets of ten tabletseach with 900 mL of a 1:2 mixture of acetonitrile and simulated gastricfluid without enzyme (SGF) under constant magnetic stirring in a 1000-mLvolumetric flask until all tablets were completely dispersed or forovernight. The sample solutions were diluted and analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC₁₈ 3.0×250 mm, 5 μm column maintained at 60° C. using amobile phase consisting of acetonitrile and potassium phosphatemonobasic buffer at pH 3.0 with UV detection at 280 nm.

Tablets cured for 30 minutes (uncoated) were subjected to the contentuniformity test. Oxycodone hydrochloride was extracted from ten separatetablets each with 90 mL of a 1:2 mixture of acetonitrile and simulatedgastric fluid without enzyme (SGF) under constant magnetic stirring in a100-mL volumetric flask until the tablets were completely dispersed orfor overnight. The sample solutions were diluted and analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC₁₈ 3.0×250 mm, 5 μm column maintained at 60° C. using amobile phase consisting of acetonitrile and potassium phosphatemonobasic buffer at pH 3.0 with UV detection at 280 nm.

The results are presented in Table 23.

TABLE 23 Example 23 30 min cure Assay 98.9 (% oxycodone HCl)¹ Contentuniformity 97.9 (% oxycodone HCl)¹ Dissolution  1 hr 26 (% Released)  2hr 42 (n = 6)  4 hr 66  8 hr 92 12 hr 101 ¹relative to the label claimof Oxycodone HCl

Example 24

In Example 24, 150 mg tablets including 2 mg Hydromorphone HCl wereprepared using high molecular weight polyethylene oxide.

Composition:

Ingredient mg/unit g/batch Hydromorphone HCl 2 66.5 Polyethylene oxide(MW: approximately 4,000,000; Polyox ™ WSR-301) 147.25 4908.5 MagnesiumStearate 0.75 25 Total Core Tablet Weight (mg) 150 Total Batch size 10kg (2 × 5 kg)

The processing steps to manufacture tablets were as follows:

-   1. A PK V-blender (with I-bar)—4 quart was charged in the following    order:

Approximately 600 g of the Polyethylene Oxide 301

Hydromorphone HCl

Approximately 600 g of the Polyethylene Oxide 301

-   2. Step 1 materials were blended for 2 minutes with the I-bar ON and    then discharged.-   3. A PK V-blender (with I-bar)—16 quart was charged in the following    order:

Approximately half of the remaining Polyethylene Oxide 301

Pre-blend material (from step 2)

Remaining Polyethylene Oxide 301

-   4. Step 3 materials were blended for 5 minutes with the intensifier    bar ON.-   5. Magnesium stearate was charged in the PK V-blender.-   6. Step 5 materials were blended for 1 minute with the intensifier    bar OFF.-   7. Step 6 blend was charged into a plastic bag (Note: two 5 kg    blends were produced to provide 10 kgs available for compression).-   8. Step 7 blend was compressed to target weight on an 8 station    rotary tablet press using 9/32 inch standard round, concave    (embossed) tooling at 40,800 tph speed using 2 kN compression force.-   9. Step 8 tablets were loaded into a 24 inch Compu-Lab coating pan    at a pan load of 9.146 kg.-   10. The pan speed was set to 10 rpm and the tablet bed was heated by    setting the inlet air temperature to achieve an exhaust temperature    of approximately 72° C. The curing starting point (as described by    method 2) was initiated once the exhaust temperature achieved 72° C.    The tablets were cured at the target exhaust temperature for 1 hour.    Tablet samples were taken after 30 minutes of curing.-   11. The pan speed was increased to 15 rpm once the exhaust    temperature reached 72° C.-   12. After 1 hour of curing at the target exhaust temperature, the    inlet temperature was set to 22° C. to initiate cooling. After 3    minutes of cooling the tablet bed massed forming large agglomerates    of tablets. Coating was not feasible.-   13. The tablets were discharged.

It is assumed that the agglomeration of tablets can be avoided, forexample by increasing the pan speed, by the use of Magnesium Stearate asanti-tacking agent, or by applying a sub-coating prior to curing.

In vitro testing including dissolution, assay and content uniformitytest was performed as follows:

Tablets cured for 30 minutes (uncoated) were tested in vitro using USPApparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluidwithout enzymes (SGF) at 37.0° C. Samples were analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC18 3.0×250 mm, 5 μm column, using a mobile phase consistingof a mixture of acetonitrile and potassium phosphate monobasic buffer(pH 3.0) at 220 nm UV detection. Sample time points include 1.0, 2.0,4.0, 8.0 and 12.0 hours.

Tablets cured for 30 minutes (uncoated) were subjected to the assaytest. Oxycodone hydrochloride was extracted from two sets of ten tabletseach with 900 mL of a 1:2 mixture of acetonitrile and simulated gastricfluid without enzyme (SGF) under constant magnetic stirring in a 1000-mLvolumetric flask until all tablets were completely dispersed or forovernight. The sample solutions were diluted and analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC₁₈ 3.0×250 mm, 5 μm column maintained at 60° C. using amobile phase consisting of acetonitrile and potassium phosphatemonobasic buffer at pH 3.0 with UV detection at 280 nm.

Tablets cured for 30 minutes (uncoated) were subjected to the contentuniformity test. Oxycodone hydrochloride was extracted from ten separatetablets each with 90 mL of a 1:2 mixture of acetonitrile and simulatedgastric fluid without enzyme (SGF) under constant magnetic stirring in a100-mL volumetric flask until the tablets were completely dispersed orfor overnight. The sample solutions were diluted and analyzed byreversed-phase high performance liquid chromatography (HPLC) on WatersAtlantis dC₁₈ 3.0×250 mm, 5 μm column maintained at 60° C. using amobile phase consisting of acetonitrile and potassium phosphatemonobasic buffer at pH 3.0 with UV detection at 280 nm.

The results are presented in Table 24.

TABLE 24 Example 24 30 min cure Assay 95.7 (67.9 oxycodone HCl)¹ Contentuniformity (% 94.9 oxycodone HCl)¹ Dissolution  1 hr 26  2 hr 39 (%Released)  4 hr 62 (n = 6)  8 hr 89 12 hr 98 ¹relative to the labelclaim of Oxycodone HCl

Example 25

In Example 25, two different 400 mg tablets including 60 mg (Example25.1 and 25.2) and 80 mg (Example 25.3 and 25.4) of oxycodone HCl wereprepared using high molecular weight polyethylene oxide and lowmolecular weight polyethylene oxide. Two 100 kg batches were preparedfor each formulation.

Example 25 mg/unit mg/unit Ingredient Oxycodone HCl 60 80 Polyethyleneoxide (MW: 229.7 216 approximately 4,000,000; Polyox ™ WSR- 301)Polyethylene oxide (MW: 106.3 100 approximately 100,000; Polyox ™ WSR-N10) Magnesium Stearate 4 4 Total Core Tablet Weight (mg) 400 400Example 25.1 25.2 25.3 25.4 Total Batch size 100 kg 100 kg 100 kg 100 kgCoating mg/unit mg/unit Opadry film coating 16 16 Total Tablet Weight(mg) 416 416 Example 25.1 25.2 25.3 25.4 Coating Batch Size (kg) 91.44096.307 95.568 98.924The processing steps to manufacture tablets were as follows:

-   1. The magnesium stearate was passed through a Sweco Sifter equipped    with a 20 mesh screen, into a separate suitable container.-   2. A Gemco “V” blender (with I bar)—10 cu. ft. was charged in the    following order:

Approximately ½ of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Polyethylene oxide WSR N10

Remaining polyethylene oxide WSR 301

-   3. Step 2 materials were blended for 10 minutes with the 1 bar on.-   4. Magnesium stearate was charged into the Gemco “V” blender.-   5. Step 4 materials were blended for 2 minutes with the I bar off.-   6. Step 5 blend was charged into a clean, tared, stainless steel    container.-   7. Step 6 blend was compressed to target weight on a 40 station    tablet press at 124,000 tph using 13/32 inch standard round, concave    (embossed) tooling.-   8. Step 7 tablets were loaded into a 48 inch Accela-Coat coating pan    at a load of 91.440 kg (Example 25.1), 96.307 kg (Example 25.2),    95.568 kg (Example 25.3) and 98.924 kg (Example 25.4).-   9. The pan speed was set at 6 to 10 rpm and the tablet bed was    warmed using an exhaust air temperature to target a 55° C. inlet    temperature. Film coating was started once the exhaust temperature    approached 40° C. and continued for 10, 15 or 16 minutes. This    initial film coat was performed to provide an “overcoat” for the    tablets to function as an anti-tacking agent during the curing    process.-   10. After completion of the “overcoat”, the tablet bed was heated by    setting the exhaust air temperature to achieve a target inlet air    temperature of 75° C. (Example 25.1 and 25.3) or to achieve a target    exhaust temperature of 78° C. (Example 25.2 and 25.4). The tablets    were cured at the target temperature for 65 minutes (Example 25.1),    52 minutes (Example 25.2), 80 minutes (Example 25.3) and 55 minutes    (Example 25.4). For Example 25.1 and 25.3, the curing starting point    (as described by method 1) was initiated once the inlet temperature    reached the target inlet temperature. For Example 25.2 and 25.4, the    curing starting point (as described by method 2) was initiated once    the exhaust temperature reached the target exhaust temperature. The    temperature profile of the curing processes of Examples 25.1 to 25.4    is presented in Tables 25.1.1 to 25.4.1.-   11. During the curing process, the pan speed was increased from 7 to    9 rpm (Example 25.1 and 25.3) and from 10 to 12 rpm (Example 25.2    and 25.4). For examples 25.1 to 25.4, 20 g of magnesium stearate was    added as an anti-tacking agent. The tablet bed was cooled by setting    the exhaust temperature setting to 30° C.-   12. After cooling, the tablet bed was warmed using an inlet setting    of 53° C. The film coating was started once the exhaust temperature    achieved approximately 39° C. and continued until the target weight    gain of 4% was achieved.-   13. After film coating was completed, the tablet bed was cooled by    setting the exhaust temperature to 27° C. The tablet bed was cooled    to an exhaust temperature of 30° C. or less was achieved.-   14. The tablets were discharged.

In vitro testing including breaking strength tests was performed asfollows.

Cured and coated tablets were tested in vitro using USP Apparatus 1(basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes(SGF) at 37° C. Samples were analyzed by reversed-phase high performanceliquid chromatography (HPLC) on Waters Atlantis dC18 3.0×150 mm, 3 μmcolumn, using a mobile phase consisting of a mixture of acetonitrile andnon basic potassium phosphate buffer (pH 3.0) at 230 nm UV detection.Sample time points include 1.0, 2.0, 4.0, 6.0, 8.0 and 12.0 hours.

Uncured tablets were subjected to a breaking strength test by applying aforce of a maximum of 196 Newton using a Schleuniger 2E 1/106 apparatusto evaluate tablet resistance to breaking.

The results are presented in Tables 25.1.2 to 25.4.2

TABLE 25.1.1 Temperature profile of the curing process for Ex. 25.1 SetActual Total Curing Inlet exhaust exhaust Pan time time temp. temp.temp. speed (min.) (min.)¹ (° C.)² (° C.) (° C.)³ (rpm) Comments 0 — 5260 41 7 5  0 75 60 59 7 Start curing 15 10 81 65 66 7 25 20 85 68 70 735 30 73 71 70 9 45 40 75 72 72 9 55 50 75 72 72 9 65 60 74 72 72 9 7065 75 72 72 9 End curing, add 20 g Mg St 71 — 74 30 72 9 Start cooling81 — 32 30 52 9 91 — 24 30 36 9 94 — 23 30 30 9 End cooling ¹determinedaccording to method 1, ²temperature measured at the inlet, ³temperaturemeasured at the exhaust.

TABLE 25.1.2 Example 25.1 Uncured cured, coated Tablet Weight (mg) 401 —Dimensions (n = 120) Breaking 112 — strength (N) (n = 50) 

TABLE 25.2.1 Temperature profile of the curing process for Ex. 25.2 SetActual Total Curing Inlet exhaust exhaust Pan time time temp. temp.temp. speed (min.) (min.)¹ (° C.)² (° C.) (° C.)³ (rpm) Comments 0 — 6965 46 10 3 — 75 65 53 10 13 — 85 70 65 10 23 — 90 75 69 10 33  0 90 7777 10 Start curing 43 10 78 77 75 10 53 20 79 77 77 10 63 30 81 77 77 1073 40 80 77 77 12 83 50 79 77 77 12 85 52 80 77 77 12 End curing, add 20g Mg St 86 — 80 30 77 12 Start cooling 96 — 37 30 54 12 106 — 29 25 4712 116 — 24 25 30 12 End cooling ¹determined according to method 2,²temperature measured at the inlet, ³temperature measured at theexhaust.

TABLE 25.2.2 Example 25.2 cured, coated cured, coated Uncured Initialdata 2^(nd) test data Tablet Weight (mg) 400 — — Dimensions (n = 120)Breaking 103 — — strength (N) (n = 40)  n = 6 n = 6 Dissolution  1 hr —23  24 (%  2 hr — 39  43 Released)  4 hr — 62  70 SGF  6 hr — 79  88  8hr — 90  99 12 hr — 97 103

TABLE 25.3.1 Temperature profile of the curing process for Ex. 25.3 SetActual Total Curing Inlet exhaust exhaust Pan time time temp. temp.temp. speed (min.) (min.)¹ (° C.)² (° C.) (° C.)³ (rpm) Comments 0 — 5565 39 7 5  0 75 65 58 7 Start curing 15 10 82 66 66 7 25 20 86 68 70 735 30 76 72 72 7 45 40 75 72 72 7 55 50 75 72 72 7 65 60 75 72 72 9 7570 74 72 72 9 85 80 74 72 72 9 End curing, add 20 g Mg St 86 — 75 30 729 Start cooling 96 — 33 30 53 9 106 — 26 30 39 9 112 — 23 30 30 9 Endcooling ¹determined according to method 1, ²temperature measured at theinlet, ³temperature measured at the exhaust.

TABLE 25.3.2 Example 25.3 cured, coated cured, coated Uncured Initialdata 2^(nd) test data Tablet Weight (mg) 400 — — Dimensions (n = 120)Thickness (mm) — — — Diameter (mm) — — — Breaking 111 — — strength (N)(n = 40)  — —

TABLE 25.4.1 Temperature profile of the curing process for Ex. 25.4 SetActual Total Curing Inlet exhaust exhaust Pan time time temp. temp.temp. speed (min.) (min.)¹ (° C.)² (° C.) (° C.)³ (rpm) Comments 0 — 6070 43 10 10 — 80 75 64 10 20 — 85 75 69 10 30 — 88 76 74 10 33  0 88 7878 10 Start curing 43 10 75 78 76 12 53 20 84 78 79 12 63 30 82 78 78 1273 40 79 78 78 12 83 50 82 78 78 12 88 55 80 78 78 12 End curing, add 20g Mg St 89 — 79 30 78 12 Start cooling 99 — 38 25 54 12 109 — 26 25 4512 113 — 23 25 34 12 End cooling ¹determined according to method 2,²temperature measured at the inlet, ³temperature measured at theexhaust.

TABLE 25.4.2 Example 25.4 cured, coated cured, coated Uncured Initialdata 2^(nd) test data Tablet Weight (mg) 400 — — Dimensions (n = 120)Thickness (mm) — — — Diameter (mm) — — — Breaking 101 — — strength (N)(n = 40) n = 6 n = 6 Dissolution  1 hr — 25  29 (%  2 hr — 42  47Released)  4 hr — 66  73 SGF  6 hr — 84  91  8 hr — 96  99 12 hr — 100 101

TABLE 25.5 Density Density (g/cm³)¹ change 30 min 60 min after Uncuredcure cure curing (%)² Example 25.1 1.205 1.153 1.138 −5.560 Example 25.31.207 1.158 1.156 −4.225 ¹The density was measured as described forExample 13. The density value is a mean value of 3 tablets measured;²The density change after curing corresponds to the observed densitychange in % of the tablets cured for 60 min in comparison to the uncuredtablets.

Example 26

In Example 26, a randomized, open-label, single-dose, four-treatment,four-period, four-way crossover study in healthy human subjects wasconducted to assess the pharmacokinetic characteristics and relativebioavailability of three oxycodone tamper resistant formulations (10 mgoxycodone HCl tablets of Examples 7.1 to 7.3 relative to the commercialOxyContin® formulation (10 mg), in the fasted and fed state.

The study treatments were as follows:

Test Treatments:

-   -   Treatment 1A: 1× Oxycodone HCl 10 mg Tablet of Example 7.3        (Formulation 1A) administered in the fasted or fed state.    -   Treatment 1B: 1× Oxycodone HCl 10 mg Tablet of Example 7.2        (Formulation 1B) administered in the fasted or fed state.    -   Treatment 1C: 1× Oxycodone HCl 10 mg Tablet of Example 7.1        (Formulation 1C) administered in the fasted or fed state.

Reference Treatment:

-   -   Treatment OC: 1× OxyContin® 10 mg tablet administered in the        fasted or fed state.

The treatments were each administered orally with 8 oz. (240 mL) wateras a single dose in the fasted or fed state.

As this study was conducted in healthy human subjects, the opioidantagonist naltrexone hydrochloride was administered to minimizeopioid-related adverse events.

Subject Selection Screening Procedures

The following screening procedures were performed for all potentialsubjects at a screening visit conducted within 28 days prior to firstdose administration:

-   -   Informed consent.    -   Weight, height, body mass index (BMI), and demographic data.    -   Evaluation of inclusion/exclusion criteria.    -   Medical and medication history, including concomitant        medication.    -   Vital signs—blood pressure, respiratory rate, oral temperature,        and pulse rate (after being seated for approximately 5 minutes)        and blood pressure and pulse rate after standing for        approximately 2 minutes—and pulse oximetry (SPO₂), including        “How do you feel?” Inquiry.    -   Routine physical examination (may alternately be performed at        Check-in of Period 1).    -   Clinical laboratory evaluations (including biochemistry,        hematology, and urinalysis [UA]).    -   12-lead electrocardiogram (ECG).    -   Screens for hepatitis (including hepatitis B surface antigen        [HBsAg], hepatitis B surface antibody [HBsAb], hepatitis C        antibody [anti-HCV]), and selected drugs of abuse.    -   Serum pregnancy test (female subjects only).    -   Serum follicle stimulating hormone (FSH) test (postmenopausal        females only)

Inclusion Criteria

Subjects who met the following criteria were included in the study.

-   -   Males and females aged 18 to 50, inclusive.    -   Body weight ranging from 50 to 100 kg (110 to 220 lbs) and a        BMI≧18 and ≦34 (kg/m²).    -   Healthy and free of significant abnormal findings as determined        by medical history, physical examination, vital signs, and ECG.    -   Females of child-bearing potential must be using an adequate and        reliable method of contraception (e.g., barrier with additional        spermicide foam or jelly, intra-uterine device, hormonal        contraception (hormonal contraceptives alone are not        acceptable). Females who are postmenopausal must have been        postmenopausal ≧1 year and have elevated serum FSH.    -   Willing to eat all the food supplied during the study.

Exclusion Criteria

The following criteria excluded potential subjects from the study.

-   -   Females who are pregnant (positive beta human chorionic        gonadotropin test) or lactating.    -   Any history of or current drug or alcohol abuse for 5 years.    -   History of or any current conditions that might interfere with        drug absorption, distribution, metabolism or excretion.    -   Use of an opioid-containing medication in the past 30 days.    -   History of known sensitivity to oxycodone, naltrexone, or        related compounds.    -   Any history of frequent nausea or emesis regardless of etiology.    -   Any history of seizures or head trauma with current sequelae.    -   Participation in a clinical drug study during the 30 days        preceding the initial dose in this study.    -   Any significant illness during the 30 days preceding the initial        dose in this study.    -   Use of any medication including thyroid hormone replacement        therapy (hormonal contraception is allowed), vitamins, herbal,        and/or mineral supplements, during the 7 days preceding the        initial dose.    -   Refusal to abstain from food for 10 hours preceding and 4 hours        following administration of the study drugs and to abstain from        caffeine or xanthine entirely during each confinement.    -   Consumption of alcoholic beverages within forty-eight (48) hours        of initial study drug administration (Day 1) or anytime        following initial study drug administration.    -   History of smoking or use of nicotine products within 45 days of        study drug administration or a positive urine cotinine test.    -   Blood or blood products donated within 30 days prior to        administration of the study drugs or anytime during the study,        except as required by this protocol.    -   Positive results for urine drug screen, alcohol screen at        Check-in of each period, and HBsAg, HBsAb (unless immunized),        anti-HCV.    -   Positive Naloxone HCl challenge test.    -   Presence of Gilbert's Syndrome or any known hepatobiliary        abnormalities.    -   The Investigator believes the subject to be unsuitable for        reason(s) not specifically stated in the exclusion criteria.

Subjects meeting all the inclusion criteria and none of the exclusioncriteria were randomized into the study. It was anticipated thatapproximately 34 subjects would be randomized, with 30 subjects targetedto complete the study. Any subject who discontinued could be replaced.

Subjects were assigned by the random allocation schedule (RAS) in a 2:1ratio to fasted or fed state, with twenty subjects to be randomized to afasted state and 10 subjects to be randomized to a fed state. Check-inProcedures

On Day −1 of Period 1, subjects were admitted to the study unit andreceived a Naloxone HCl challenge test. The results of the test had tobe negative for subjects to continue in the study. Vital signs and SPO₂were measured prior to and following the Naloxone HCl.

The following procedures were also performed for all subjects atCheck-in for each period:

-   -   Verification of inclusion/exclusion criteria, including        verification of willingness to comply with caffeine or xanthine        restriction criteria.    -   Routine physical examination at Check-in of Period 1 only (if        not performed at Screening).    -   Vital signs-blood pressure, respiratory rate, and pulse rate        (after being seated for approximately 5 minutes) and SPO₂,        including How Do You Feel? Inquiry.    -   Screen for alcohol (via breathalyzer test), cotinine, and        selected drugs of abuse.    -   Urine pregnancy test (for all female subjects).    -   Verification of medication and medical history.    -   Concomitant medication monitoring and recording.    -   Adverse Event monitoring and recording.

For subjects to continue their participation in the study, the resultsof the drug screen (including alcohol and cotinine) had to be availableand negative prior to dosing. In addition, continued compliance withconcomitant medication and other restrictions were verified at Check-inand throughout the study in the appropriate source documentation.

Prior to the first dose in Period 1, subjects were randomized to atreatment sequence in which test and reference treatments are receivedin a specified order. The treatment sequence according to the randomallocation schedule (RAS) was prepared by a biostatistician who was notinvolved in the evaluation of the results of the study. Randomizationwas used in this study to enhance the validity of statisticalcomparisons across treatments.

The treatment sequences for this study are presented in Table 26.1:

TABLE 26.1 Period 1 Period 2 Period 3 Period 4 Sequence Treatment 1 OC1C 1A 1B 2 1A OC 1B 1C 3 1B 1A 1C OC 4 1C 1B OC 1A

Study Procedures

The study included four study periods, each with a single doseadministration. There was a washout period of seven days between doseadministrations in each study period. During each period, subjects wereconfined to the study site from the day prior to administration of thestudy drugs through 48 hours following administration of the studydrugs, and returned to the study site for 72-hour procedures.

At each study period, the subjects were administered one of the testoxycodone formulations (10 mg) or OxyContin® 10 mg tablets (OC) with 240mL of water, following a 10 hour overnight fast (for fasted treatments).Subjects receiving fasted treatments continued fasting from food for 4hours following dosing. Subjects receiving fed treatments started thestandard meal (FDA high-fat breakfast) 30 minutes prior toadministration of the drug.

Subjects were dosed 30 minutes after start of the meal and no food wasallowed for at least 4 hours post-dose.

Subjects received naltrexone HCl 50 mg tablets at −12, 0, 12, 24, and 36hours relative to each test formulation or OxyContin® dosing.

Subjects were standing or in an upright sitting position while receivingtheir dose of study medication. Subjects remained in an upright positionfor a minimum of 4 hours.

Clinical laboratory sampling was preceded by a fast (i.e. at least 10hours) from food (not including water). Fasting was not required fornon-dosing study days.

During the study, adverse events and concomitant medications wererecorded, and vital signs (including blood pressure, body temperature,pulse rate, and respiration rate) and SPO₂ were monitored.

Blood samples for determining oxycodone plasma concentrations wereobtained for each subject at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5,4, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours postdose foreach period.

For each sample, 6 mL of venous blood were drawn via an indwellingcatheter and/or direct venipuncture into tubes containing K₂EDTAanticoagulant (6 mL-draw K₂EDTA Vacutainer® evacuated collection tubes).Plasma concentrations of oxycodone were quantified by a validated liquidchromatography tandem mass spectrometric method.

Study Completion Procedures

The following procedures were performed in the clinic for all subjectsat End of Study (Study Completion) or upon discontinuation from thestudy:

-   -   Concomitant medication evaluation.    -   Vital signs and SPO₂, including How Do You Feel? inquiry.    -   Physical examination.    -   12-Lead ECG.    -   Clinical laboratory evaluations (including biochemistry [fasted        at least 10 hours], hematology, and urinalysis).    -   Adverse event evaluations.    -   Serum pregnancy test (for female subjects only).

The results of this study are shown in Tables 26.2 to 26.5.

TABLE 26.2 Mean plasma pharmacokinetic metrics data Treatments 1A, 1B,1C and OC (fed state) C_(max) t_(max) AUC_(t) AUC_(inf) t_(1/2z) λ_(z)t_(lag) (ng/mL) (hr) (ng · hr/mL) (ng · hr/mL) (hr) (1/hr) (hr)Treatment 1A-fed N 12 12 12 11 12 12 12 MEAN 11.3 5.08 122 134 4.220.170 0.0833 SD 5.54 2.46 55.3 42.5 0.884 0.0292 0.195 MIN 0.372 1.001.13 86.2 3.34 0.114 0 MEDIAN 10.7 5.00 120 121 3.94 0.177 0 MAX 20.510.0 221 223 6.10 0.207 0.500 GEOMEAN 8.63 NA 85.8 128 NA NA NATreatment 1B-fed N 12 12 12 12 12 12 12 MEAN 14.2 5.25 133 134 4.370.164 0.0833 SD 3.36 1.48 40.2 40.3 0.947 0.0283 0.195 MIN 8.11 3.0063.7 64.5 3.28 0.0990 0 MEDIAN 14.2 5.00 126 127 4.22 0.165 0 MAX 18.58.00 205 207 7.00 0.211 0.500 GEOMEAN 13.8 NA 127 128 NA NA NA Treatment1C-fed N 12 12 12 12 12 12 12 MEAN 17.1 4.21 138 139 4.41 0.162 0.0417SD 4.66 1.21 42.9 42.9 0.843 0.0263 0.144 MIN 11.6 1.50 91.4 92.5 3.430.107 0 MEDIAN 16.5 4.50 122 123 4.03 0.173 0 MAX 27.9 6.00 218 219 6.490.202 0.500 GEOMEAN 16.5 NA 133 134 NA NA NA Treatment OC-fed N 12 12 1212 12 12 12 MEAN 13.2 3.17 142 143 4.83 0.146 0 SD 3.20 1.85 39.3 39.50.702 0.0189 0 MIN 8.85 1.00 95.2 95.9 3.93 0.105 0 MEDIAN 12.3 2.25 124125 4.76 0.146 0 MAX 18.1 6.00 218 219 6.59 0.176 0 GEOMEAN 12.8 NA 137138 NA NA NA NA = not applicable.

TABLE 26.3 Mean plasma pharmacokinetic metrics data Treatments 1A, 1B,1C and OC (fasted state) C_(max) t_(max) AUC_(t) AUC_(inf) t_(1/2z)λ_(z) t_(lag) (ng/mL) (hr) (ng · hr/mL) (ng · hr/mL) (hr) (1/hr) (hr)Treatment 1A-fasted N 20 20 20 20 20 20 20 MEAN 8.84 4.60 109 111 4.660.156 0.0250 SD 2.25 1.90 20.1 20.3 1.26 0.0279 0.112 MIN 4.85 2.00 69.069.8 3.56 0.0752 0 MEDIAN 8.53 5.00 114 114 4.29 0.162 0 MAX 13.2 10.0138 139 9.22 0.195 0.500 GEOMEAN 8.56 NA 108 109 NA NA NA Treatment1B-fasted N 19 19 19 19 19 19 19 MEAN 9.97 4.58 115 116 4.67 0.156 0 SD1.82 1.18 23.8 23.8 1.24 0.0309 0 MIN 6.90 2.00 75.2 76.3 3.53 0.0878 0MEDIAN 10.0 5.00 121 122 4.35 0.159 0 MAX 14.1 6.00 152 153 7.90 0.197 0GEOMEAN 9.81 NA 113 114 NA NA NA Treatment 1C-fasted N 22 22 22 22 22 2222 MEAN 13.6 3.75 110 111 4.18 0.169 0.0227 SD 3.79 1.38 18.5 18.5 0.5940.0256 0.107 MIN 8.64 1.00 70.6 71.1 2.92 0.135 0 MEDIAN 12.9 3.75 112113 4.13 0.169 0 MAX 23.7 6.00 142 143 5.14 0.237 0.500 GEOMEAN 13.2 NA108 109 NA NA NA Treatment OC-fasted N 19 19 19 19 19 19 19 MEAN 9.732.82 114 115 4.82 0.154 0 SD 1.67 0.960 26.0 26.2 1.41 0.0379 0 MIN 7.381.00 76.3 77.8 3.11 0.0839 0 MEDIAN 9.57 3.00 112 112 4.37 0.159 0 MAX13.2 5.00 181 183 8.27 0.223 0 GEOMEAN 9.60 NA 112 113 NA NA NA NA = notapplicable.

TABLE 26.4 Statistical Results of Oxycodone Pharmacokinetic Metrics:Bioavailability Example 7.1 to 7.3 Tablets Relative to OxyContin ® 10 mgin the Fed State (Population: Full Analysis) Cmax AUCt LS Mean LS MeanComparison Ratio 90% Ratio 90% (Test (test/ Confidence (test/ Confidencevs. Ref) reference)^(a) Interval^(b) reference)^(a) Interval^(b) 1A vs.OC 67.5 [47.84, 95.16] 62.6 [39.30, 99.83] 1B vs. OC 108.0 [76.59,152.33] 92.9 [58.31, 148.14] 1C vs. OC 129.0 [91.54, 182.07] 97.0[60.83, 154.52] ^(a)Least squares mean from ANOVA. Natural log (ln)metric means calculated by transforming the ln means back to the linearscale, i.e., geometric means; Ratio of metric means for ln-transformedmetric (expressed as a percent). Ln-transformed ratio transformed backto linear scale (test = Treatment 1A, 1B, 1C; reference = Treatment OC);^(b)90% confidence interval for ratio of metric means (expressed as apercent). Ln-transformed confidence limits transformed hack to linearscale.

TABLE 26.5 Statistical Results of Oxycodone Pharmacokinetic Metrics:Bioavailability Example 7.1 to 7.3 Tablets Relative to OxyContin ® 10 mgin the Fasted State (Population: Full Analysis) Cmax AUCt LS Mean LSMean Comparison Ratio 90% Ratio 90% (Test (test/ Confidence (test/Confidence vs. Ref) reference)^(a) Interval^(b) reference)^(a)Interval^(b) 1A vs. OC 89.5 [82.76, 96.89] 97.0 [92.26, 102.79] 1B vs.OC 99.0 [91.33, 107.30] 101.0 [95.42, 106.57] 1C vs. OC 133.0 [123.23,143.86] 96.4 [91.43, 101.68] ^(a)Least squares mean from ANOVA. Naturallog (ln) metric means calculated by transforming the ln means back tothe linear scale, i.e., geometric means; Ratio of metric means forln-transformed metric (expressed as a percent). Ln-transformed ratiotransformed back to linear scale (test = Treatment 1A, 1B, 1C; reference= Treatment OC); ^(b)90% confidence interval for ratio of metric means(expressed as a percent). Ln-transformed confidence limits transformedback to linear scale.

Example 27

In Example 27, oxycodone HCl tablets of Example 7.2, and Example 14.2 to14.5 containing 10, 15, 20, 30, and 40 mg oxycodone HCl respectivelywere subjected to a variety of tamper resistance testing, usingmechanical force and chemical extraction to evaluate their resistance tophysical and chemical manipulation.

Test results are compared to control data, defined as percent ActivePharmaceutical Ingredient (API) released for intact tablets after invitro dissolution in Simulated Gastric Fluid without enzyme (SGF) for 45minutes. This comparator was chosen as a reference point to approximatethe amount of API present in the body (after 45 min) when the product istaken as directed. Available results for the current marketedformulation, OxyContin™, are presented for comparison as well.

Five different strength tablets (10, 15, 20, 30 and 40 mg oxycodone HCl,corresponding to Example 7.2, and Examples 14.2 to 14.5) weremanufactured. All tablet strengths are about the same size and weight,therefore all testing was performed on the bracketing tablet strengthswith the lowest API to excipient ratio (10 mg, Example 7.2) and thehighest API to excipient ratio (40 mg, Example 14.5). In addition, level1 testing was performed on the intermediate tablet strengths (15, 20 and30 mg, Examples 14.2, 14.3 and 14.4) to assess the resistance tophysical manipulation, and subsequent chemical extraction, when using amortar and pestle. Further testing was not performed on these tablets ashigher levels of testing employ a coffee mill which resulted in similarparticle size distributions and similar amount of extracted API for themilled bracketing tablets (Example 7.2 and 14.5). The experimentaltechniques used for this testing were designed to provide procedures forsimulating and evaluating common methods of abuse. Four levels of tamperresistance were broadly defined to provide an approximation of therelative level of tamper resistance. Several approaches to tamperingwere considered; these include mechanical force (applied to damage thedrug product), availability and toxicity of extraction solvents, lengthof extraction, and thermal treatment. Each higher level of tamperresistance represents an increase in the degree of difficulty necessaryto successfully tamper with a drug product. The definitions of levels oftamper resistance, including examples of equipment and reagents, arepresented in Table 27.1.

TABLE 27.1 Definitions and Examples of Testing Degree Of EquipmentReagent Level Definition Difficulty Examples Examples 0 Able to bedirectly abused Negligible N/A None without preparation 1 Readily abusedthrough a Minimal Crushing tool water, variety of means without reagent(hammer, shoe, distilled spirits or with an easily obtainable pillcrusher, etc) (vodka, gin, etc), reagent vinegar, Reagents are directlyingestible baking soda, and extraction time is shorter cooking oil 2Readily abused with additional Moderate Tools for IV 100% ethanol (grainpreparation requiring some preparation, alcohol, Everclear) planningmilling tool strong acidic and Reagents are directly ingestible, (coffeemill, basic solutions although more harmful, blender), extraction timeis shorter, and microwave oven thermal treatment is applied 3Preparation for abuse requires Substantial Impact mill In addition toknowledge of drug chemistry, (e.g., Fitzmill) previously listed includesless readily available solvents: reagents, may require industrialmethanol, tools, involves complex ether, processes (e.g., two-phaseisopropanol, extraction) acetone, Some reagents are harmful and ethylacetate not directly ingestible, extraction time and temperature areincreased

Testing Results Control Data (“Taken as Directed”) and SpecificationLimits

Dissolution testing on intact Example 7.2, and Example 14.2 to 14.5tablets was performed in vitro using USP Apparatus 1 (basket) at 100 rpmin 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.Samples were taken at 45 minutes of dissolution and analyzed byreversed-phase high performance liquid chromatography (HPLC). Theaverage results of a triplicate analysis are reported in Table 27.2 andcompared to equivalent data for OxyContin™ 10 mg tablets.

TABLE 27.2 Control Results - % API Released at 45 minutes % oxycodoneHCl¹ released at 45 minutes OxyContin ™ Ex. 7.2 Ex. 14.2 Ex. 14.3 Ex.14.4 Ex. 14.5 Sample Preparation 10 mg (10 mg) (15 mg) (20 mg) (30 mg)(40 mg) None (intact tablets) 34 19 20 20 18 19 ¹relative to label claim

In addition, Table 27.3 contains the one hour dissolution specificationlimits for each of the tablets studied. This illustrates the range ofacceptable drug release at one hour for all formulations tested in thisstudy. It should be noted that the upper acceptable limit for one hourin vitro release of oxycodone HCl from OxyContin 10 mg tablets is 49%.

TABLE 27.3 Dissolution (% Released) Specification Limits Product 1 HrSpecification Limit Example 7.2 15-35 Example 14.2 15-35 Example 14.315-35 Example 14.4 15-35 Example 14.5 15-35 OxyContin ™ 10 mg 29-49

Level 1 Testing

Level one testing included crushing with a mortar and pestle and simpleextraction.

Level 1 Results—Crushing

After crushing in a mortar and pestle, in vitro dissolution testing wasperformed in triplicate for each product using USP Apparatus 1 (basket)at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at37° C., as described above for control data. Example 7.2 tablets werenot able to be crushed using a mortar and pestle and therefore releaseof the API was not significantly increased as compared to the controlresults. Although difficult, tablets of Examples 14.2 to 14.5 (15, 20,30 and 40 mg tablets) could be broken into large pieces using a mortarand pestle producing little to no powder. This reduction in particlesize resulted in higher release of the API; however, the swelling of thetablet matrix, when dissolved in SGF, provides protection against dosedumping as less than half of the API was released after 45 minutes. TheOxyContin™ tablets were easily reduced to a powder using a mortar andpestle resulting in release of most of the API. FIG. 40 containsrepresentative images of crushed tablets. Table 27.4 contains theaverage results for percent API released after crushing.

TABLE 27.4 Crushing Results - % API Released at 45 Minutes % oxycodoneHCl¹ released at 45 min. OxyContin ™ Ex. 7.2 Ex. 14.2 Ex. 14.3 Ex. 14.4Ex. 14.5 Sample Preparation 10 mg (10 mg) (15 mg) (20 mg) (30 mg) (40mg) Crushed tablets 92 20 41 44 42 43 Control - intact tablets 34 19 2020 18 19 (45 min release) ¹relative to label claim

Additionally, Example 14.5 tablets could not be crushed between twospoons demonstrating that additional tools would need to be employed tocrush the tablets. Conversely, the OxyContin™ tablets were easilycrushed between two spoons.

Level 1 Results—Simple Extraction

Example 7.2, and Example 14.2 to 14.5 tablets were crushed in a mortarand pestle and vigorously shaken on a wrist-action shaker, over a 10°angle, for 15 minutes in various solvents at room temperature. Aspreviously stated, Example 7.2 tablets were unaffected by crushing in amortar and pestle and therefore extraction amounts were not increased.Example 14.2 to 14.5 tablets were crushed using a mortar and pestlebefore extraction. Due to the swelling of the tablet matrix in thesolvents tested, the crushed tablets remained resistant to comprehensivedose dumping, whereas the OxyContin™ tablets released nearly all of theAPI. Table 27.5 contains the average amount of API released in eachsolvent.

TABLE 27.5 Simple Extraction Results - % API Released at 15 Minutes %oxycodone HCl¹ released Crushed Tablets in OxyContin ™ Ex. 7.2 Ex. 14.2Ex. 14.3 Ex. 14.4 Ex. 14.5 Extraction Solvent (10 mg) (10 mg) (15 mg)(20 mg) (30 mg) (40 mg) Water 92 8 32 30 28 51 40% EtOH (v/v) 101 5 2418 22 40 Vinegar 102 11 28 35 41 54 Cooking Oil 79 0 2 1 2 6 0.026MBaking Soda 95 6 26 25 29 50 Solution Control - intact tablets 34 19 2020 18 19 (45 min release) ¹relative to label claim

Level 2 Testing

Level two testing included milling, simulated intravenous (IV)preparation, thermal treatment and extraction.

Level 2 Results—Milling

Example 7.2 and Example 14.5 tablets were ground in a Cuisanart® coffeemill with stainless steel blades (model DCG-12BC) for 1 minute. Theenergy output of the coffee mill (1 minute) was determined to be 10.5kJ. In triplicate, material equivalent to one dosage unit was removedand analyzed by dissolution testing using USP Apparatus 1 (basket) at100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°C., as described above for the control data. After one minute, Example7.2 and Example 14.5 tablets were milled to similar particle sizedistributions resulting in both tablet strengths releasing approximatelyhalf of the API. The OxyContin™ tablets were milled into a mixture oflarger pieces and some powder resulting in nearly complete release ofthe API. Table 27.6 contains the average amount of API released from themilled tablets. As previously mentioned, the ground Example 7.2 and 14.5tablets swell and become gelatinous. This phenomenon provides protectionagainst dose dumping. FIG. 41 contains representative images of milledtablets before and after dissolution.

TABLE 27.6 Milling Results-% API Released at 45 Minutes % oxycodone HCl¹released Sample OxyContin Ex. 7.2 Ex. 14.5 Preparation (10 mg) (10 mg)(40 mg) Milled tablets 93 47 52 Control-intact tablets 34 19 19 (45 minrelease) ¹relative to label claim

Relative In Vitro Dissolution Rate

To assess the relative rate of release of the API, dissolution sampleswere collected every five minutes from t=0 to t=40 minutes for milled Ex7.2 tablets (coffee mill) and crushed OxyContin™ 10 mg tablets (mortarand pestle). The OxyContin™ tablet is more easily and effectivelycrushed using a mortar and pestle. Although approximately half of theAPI is released from milled Example 7.2 tablets over 45 minutes, it isreleased at a gradual rate that is characteristic of a controlledreleased product. Dose dumping is not observed. Conversely, dissolutionof milled OxyContin™ tablets results in complete dose dumping within 10minutes. This is illustrated in FIG. 42.

Particle Size Distribution of Milled Tablets

Milled Example 7.2 and 14.5 tablets (coffee mill) and crushed OxyContin™10 mg tablets (mortar and pestle) were analyzed by sieving to evaluatethe particle size distribution of the milled material. The tablets weresieved for 12 minutes using vibration. The sieves used and thecorresponding mesh sizes are presented in Table 27.7. As shown in theparticle size distribution graphs in FIG. 43, 70-80% of the milledExample 7.2 and 14.5 tablets are larger than 600 μm. The large particlesize of the milled material is likely disagreeable to snorting.OxyContin™ 10 mg resulted in a much smaller particle size distribution.

TABLE 27.7 Sieve Sizes and Corresponding Mesh Size Sieve Number MeshSize (μm) 30 600 40 425 60 250 80 180 120 125 200 75 325 45

Level 2 Results—Simulated Intravenous Preparation

Example 7.2 and 14.5 tablets were milled in the coffee mill (asdescribed above) and placed onto a spoon. The OxyContin™ 10 mg tabletswere crushed between two spoons. Two milliliters of water were added toeach spoon to extract or dissolve the drug product. The milled Example7.2 and 14.5 tablets became viscous after the water was added whichresulted in a small amount (<0.3 ml) of the liquid being able to bedrawn into an insulin syringe and analyzed for API content. Very littleAPI was recovered. Approximately one milliliter containing half of theAPI was recovered for the crushed OxyContin 10 mg tablets. Table 27.8contains the simulated intravenous preparation results.

TABLE 27.8 Simulated IV Results-% API Released % oxycodone HCl¹ releasedSample OxyContin ™ Ex. 7.2 Ex. 14.5 Preparation (10 mg) (10 mg) (40 mg)Simulated IV prep 49 1 4 Control-intact tablets 34 19 19 (45 minrelease) ¹relative to label claim

Level 2 Results—Thermal Treatment

Thermal treatment was attempted in the microwave; however, testing wasunsuccessful in small volumes of water. The milled Example 7.2 and 14.5tablet material could not be contained in 10-20 ml of boiling watertherefore the amount of water was increased to 100 ml. After 3 minutesat high power in an 800 Watt microwave oven (GE Model JE835), theremaining liquid was analyzed for API content. Additionally, extractionin a small amount of boiling water was assessed by adding 10 ml ofboiling water to a vial containing a milled tablet. The vial wasvigorously shaken for 15 minutes. As shown in Table 27.9, after applyingthermal treatment the milled tablet retained controlled releaseproperties that prevented complete dose dumping. The microwaveexperiment was not performed on crushed OxyContin tablets; however,comparison data from the boiling water experiment is presented.

TABLE 27.9 Thermal Treatment Results-% API Released % oxycodone IICl¹released Sample OxyContin Ex. 7.2 Ex. 14.5 Preparation (10 mg) (10 mg)(40 mg) Milled tablets in 100 ml hot water N/A 44 52 (microwave 3 min)Milled tablets with 10 ml hot water 89 58 61 (15 minutes shaken)Control-intact tablets 34 19 19 (45 min release) ¹relative to labelclaim

Level 2 Results—Extraction

Example 7.2 and 14.5 tablets were milled in a coffee mill (as per themethod described above) and subsequently shaken for 15 minutes invarious solvents at room temperature. The OxyContin™ tablets werecrushed using a mortar and pestle. Table 27.10 contains the averageamount of API released in each solvent. The milled tablets remainedresistant to comprehensive dose dumping in a variety of solvents.

TABLE 27.10 Extraction Results-% API Released at 15 Minutes % oxycodoneHCl¹ released Milled Tablets with OxyContin Ex. 7.2 Ex. 14.5 ExtractionSolvent (10 mg) (10 mg) (40 mg) 100% EtOH 96 53 48 0.1N HCl 97 45 510.2N NaOH 16 27 17 Control-intact tablets 34 19 19 (45 min release)¹relative to label claim

Level 3 Testing

Level 3 testing included extraction for 60 minutes at Room Temperature(RT) and 50° C.

Level 3 Results—Advanced Extraction (RT, 50° C.)

Example 7.2 and 14.5 tablets were milled in a coffee mill (as per themethod described above) and subsequently vigorously shaken for 60minutes in various solvents at room temperature. Additionally, themilled tablets were extracted in various solvents held at 50° C. for 60minutes using a heated water bath. Stir bars were placed in each vial toagitate the liquid. After one hour of extraction the ground tabletsretained some controlled release properties that provided protectionagainst complete dose dumping. Extraction at elevated temperatures isnot significantly more effective due to the increased solubility of thetablet matrix at higher temperatures in most of the solvents tested. InTable 27.11, amounts released for Example 7.2 and 14.5 tablets arecompared to 15 minute extraction for crushed OxyContin™ 10 mg tablets.

TABLE 27.11 Advanced Extraction Results - % API Released at 60 MinutesMilled Tablets % Oxycodone¹ Released (RT) % Oxycodone¹ Released (50° C.)with *OxyContin Ex. 7.2 Ex. 14.5 *OxyContin Ex. 7.2 Ex. 14.5 ExtractionSolvent (10 mg) (10 mg) (40 mg) 10 mg (10 mg) (40 mg) 40% Ethanol (v/v)101 55 56 N/A 61 65 100% Ethanol 96 66 61 78 67 Cooking Oil 79 2 4 7 40.1N HCl 97 58 62 62 69 0.2N NaOH 16 38 35 41 17 70% isopropanol 97 4835 49 69 (v/v) Acetone 60 37 38 N/A N/A Methanol 92 71 82 72 61 EthylAcetate 83 25 5 39 30 Ether 78 10 2 N/A N/A Control - intact 34 19 19 3419 19 tablets (45 min release) ¹relative to label claim; *CrushedOxyContin data at 15 min for comparison.

Example 28

In Example 28, a randomized, open-label, single-center, single-dose,two-treatment, two-period, two-way crossover study in healthy humansubjects was conducted to assess the bioequivalence of Example 14.1oxycodone HCl (10 mg) formulation relative to the commercial OxyContin®formulation (10 mg) in the fed state.

The study treatments were as follows:

Test treatment: 1× Example 14.1 tablet (10 mg oxycodone HCl)Reference treatment: 1× OxyContin® 10 mg tablet

The treatments were each administered orally with 8 oz. (240 mL) wateras a single dose in the fed state.

As this study was conducted in healthy human subjects, the opioidantagonist naltrexone hydrochloride was administered to minimizeopioid-related adverse events.

Subject Selection

Screening procedures were performed as described for Example 26.

Subjects who met the inclusion criteria as described for Example 26 wereincluded in the study. Potential subjects were excluded from the studyaccording to the exclusion criteria as described for Example 26, exceptthat item 11 of the exclusion criteria for this study refers to “refusalto abstain from food for 4 hours following administration of the studydrugs and to abstain from caffeine or xanthine entirely during eachconfinement.”

Subjects meeting all the inclusion criteria and none of the exclusioncriteria were randomized into the study. It was anticipated thatapproximately 84 subjects would be randomized, with approximately 76subjects targeted to complete the study.

Check-in Procedures

The check-in procedures performed on day −1 of period 1 and at check-infor each period were performed as described in Example 26. Pre-dose (Day−1, Period 1 only) laboratory samples (hematology, biochemistry, andurinalysis) were collected after vital signs and SPO₂ had been measuredfollowing overnight fasting (10 hours).

Prior to the first dose in Period 1, subjects were randomized to atreatment sequence according to the random allocation schedule (RAS) asdescribed for Example 26. The treatment sequences for this study arepresented in Table 28.1.

TABLE 28.1 Period 1 Period 2 Sequence Treatment 1 1× OxyContin ® 10 mg1× Example 14.1 2 1× Example 14.1 1× OxyContin ® 10 mg

Study Procedures

The study included two study periods, each with a single doseadministration. There was a washout period of at least six days betweendose administrations in each study period. During each period, subjectswere confined to the study site from the day prior to administration ofthe study drugs through 48 hours following administration of the studydrugs, and subjects returned to the study site for 72-hour procedures.

At each study period, following a 10 hour overnight fast, the subjectswere fed a standard meal (FDA high-fat breakfast) 30 minutes prior toadministration of either Example 14.1 formulation or OxyContin® 10 mgtablets with 240 mL of water. No food was allowed for at least 4 hourspost-dose.

Subjects received naltrexone HCl 25 mg tablets at −12, 0, and 12 hoursrelative to Example 14.1 formulation or OxyContin® dosing.

Subjects were standing or in an upright sitting position while receivingtheir dose of Example 14.1 formulation or OxyContin®. Subjects remainedin an upright position for a minimum of 4 hours.

Fasting was not required for non-dosing study days.

During the study, adverse events and concomitant medications wererecorded, and vital signs (including blood pressure, body temperature,pulse rate, and respiration rate) and SPO₂ were monitored.

Blood samples for determining oxycodone plasma concentrations wereobtained for each subject at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5,4, 4.5, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours postdosefor each period.

For each sample, 6 mL of venous blood were drawn via an indwellingcatheter and/or direct venipuncture into tubes containing K₂EDTAanticoagulant. Plasma concentrations of oxycodone were quantified by avalidated liquid chromatography tandem mass spectrometric method.

The study completion procedures were performed as described for Example26.

The results of this study are shown in Table 28.2.

TABLE 28.2 Statistical Results of Oxycodone Pharmacokinetic Metrics:Bioavailability Example 14.1 Formulation Relative to OxyContin ® 10 mgin the Fed State (Population: Full Analysis) LS Mean^(a) 90% ConfidenceMetric N (Test)^(b) N (Reference)^(b) Test/Reference^(c) Interval^(d)C_(max) (ng/mL) 79 13.9 81 13.3 105 (101.06; 108.51) AUC_(t) (ng *hr/mL) 79 138 81 145 95.7 (93.85; 97.68) AUC_(inf) 79 139 81 146 95.6(93.73; 97.53) (ng * hr/mL) ^(a)Least squares mean from ANOVA. Naturallog (ln) metric means calculated by transforming the ln means back tothe linear scale, i.e., geometric means. ^(b)Test = Example 14.1 tablet;Reference = OxyContin ® 10 mg tablet. ^(c)Ratio of metric means forln-transformed metric (expressed as a percent). Ln-transformed ratiotransformed back to linear scale. ^(d)90% confidence interval for ratioof metric means (expressed as a percent). Ln-transformed confidencelimits transformed back to linear scale.

The results show that Example 14.1 tablets are bioequivalent toOxyContin® 10 mg tablets in the fed state.

Example 29

In Example 29, a randomized, open-label, single-center, single-dose,two-treatment, two-period, two-way crossover study in healthy humansubjects was conducted to assess the bioequivalence of Example 14.1oxycodone IITC1 (10 mg) formulation relative to the commercialOxyContin® formulation (10 mg) in the fasted state.

The study treatments were as follows:

Test treatment: 1× Example 14.1 tablet (10 mg oxycodone HCl)Reference treatment: 1× OxyContin® 10 mg tablet

The treatments were each administered orally with 8 oz. (240 mL) wateras a single dose in the fasted state.

As this study was conducted in healthy human subjects, the opioidantagonist naltrexone hydrochloride was administered to minimizeopioid-related adverse events.

Subject Selection

Screening procedures were performed as described for Example 26.

Subjects who met the inclusion criteria as described for Example 26 wereincluded in the study. Potential subjects were excluded from the studyaccording to the exclusion criteria as described for Example 26.

Subjects meeting all the inclusion criteria and none of the exclusioncriteria were randomized into the study. It was anticipated thatapproximately 84 subjects would be randomized, with approximately 76subjects targeted to complete the study.

Check-in Procedures

The check-in procedures performed on day −1 of period 1 and at check-infor each period were performed as described in Example 26. Pre-dose (Day−1, Period 1 only) laboratory samples (hematology, biochemistry, andurinalysis) were collected after vital signs and SPO₂ had been measuredfollowing overnight fasting (10 hours).

Prior to the first dose in Period 1, subjects were randomized to atreatment sequence according to the random allocation schedule (RAS) asdescribed for Example 26. The treatment sequences for this study arepresented in Table 29.1.

TABLE 29.1 Period 1 Period 2 Sequence Treatment 1 1× OxyContin ® 10 mg1× Example 14.1 2 1× Example 14.1 1× OxyContin ® 10 mg

Study Procedures

The study included two study periods, each with a single doseadministration. There was a washout period of at least six days betweendose administrations in each study period. During each period, subjectswere confined to the study site from the day prior to administration ofthe study drugs through 48 hours following administration of the studydrugs, and subjects returned to the study site for 72-hour procedures.

At each study period, the subjects were administered the Example 14.1formulation or OxyContin® 10 mg tablets with 240 mL of water, followinga 10 hour overnight fast. Subjects continued fasting from food for atleast 4 hours post-dose.

Subjects received naltrexone HCl 25 mg tablets at −12, 0, and 12 hoursrelative to Example 14.1 formulation or OxyContin® dosing.

Subjects were standing or in an upright sitting position while receivingtheir dose of Example 14.1 formulation or OxyContin®. Subjects remainedin an upright position for a minimum of 4 hours.

Clinical laboratory sampling (Day −1) was preceded by a fast (i.e. atleast 10 hours) from food (not including water). Fasting was notrequired for non-dosing study days.

During the study, adverse events and concomitant medications wererecorded, and vital signs (including blood pressure, body temperature,pulse rate, and respiration rate) and SPO₂ were monitored.

Blood samples for determining oxycodone plasma concentrations wereobtained for each subject at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5,4, 4.5, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours postdosefor each period.

For each sample, 6 mL of venous blood were drawn via an indwellingcatheter and/or direct venipuncture into tubes containing K₂EDTAanticoagulant. Plasma concentrations of oxycodone were quantified by avalidated liquid chromatography tandem mass spectrometric method.

The study completion procedures were performed as described for Example26.

The results of this study are shown in Table 29.2.

TABLE 29.2 Statistical Results of Oxycodone Pharmacokinetic Metrics:Bioavailability Example 14.1 Formulation Relative to OxyContin ® 10 mgin the Fasted State (Population: Full Analysis) 90% LS Mean^(a) Test/Confidence Metric N (Test)^(b) N (Reference)^(b) Reference^(c)Interval^(d) C_(max) 81 9.36 81 9.15 102 (99.35, 105.42) (ng/mL) AUC_(t)81 107 81 109 98.3 (95.20, 101.48) (ng * hr/ mL) AUC_(inf) 81 108 81 11098.0 (94.94, 101.19) (ng * hr/ mL) ^(a)Least squares mean from ANOVA.Natural log (ln) metric means calculated by transforming the ln meansback to the linear scale, i.e., geometric means. ^(b)Test = Example 14.1tablet; Reference = OxyContin ® 10 mg tablet. ^(c)Ratio of metric meansfor ln-transformed metric (expressed as a percent). Ln-transformed ratiotransformed back to linear scale. ^(d)90% confidence interval for ratioof metric means (expressed as a percent). Ln-transformed confidencelimits transformed back to linear scale.

The results show that Example 14.1 tablets are bioequivalent toOxyContin® 10 mg tablets in the fasted state.

Example 30

In Example 30, a randomized, open-label, single-center, single-dose,two-treatment, two-period, two-way crossover study in healthy humansubjects was conducted to assess the bioequivalence of Example 14.5oxycodone HCl (40 mg) formulation relative to the commercial OxyContin®formulation (40 mg) in the fed state.

The study treatments were as follows:

Test treatment: 1× Example 14.5 tablet (40 mg oxycodone HCl)Reference treatment: 1× OxyContin® 40 mg tablet

The treatments were each administered orally with 8 oz. (240 mL) wateras a single dose in the fed state.

As this study was conducted in healthy human subjects, the opioidantagonist naltrexone hydrochloride was administered to minimizeopioid-related adverse events.

Subject Selection

Screening procedures were performed as described for Example 26.

Subjects who met the inclusion criteria as described for Example 26 wereincluded in the study. Potential subjects were excluded from the studyaccording to the exclusion criteria as described for Example 26, exceptthat item 11 of the exclusion criteria for this study refers to “refusalto abstain from food for 4 hours following administration of the studydrugs and to abstain from caffeine or xanthine entirely during eachconfinement.”

Subjects meeting all the inclusion criteria and none of the exclusioncriteria were randomized into the study. It was anticipated thatapproximately 84 subjects would be randomized, with approximately 76subjects targeted to complete the study.

Check-in Procedures

The check-in procedures performed on day −1 of period 1 and at check-infor each period were performed as described in Example 26. Pre-dose (Day−1, Period 1 only) laboratory samples (hematology, biochemistry, andurinalysis) were collected after vital signs and SPO₂ had been measuredfollowing fasting for a minimum of 4 hours.

Prior to the first dose in Period 1, subjects were randomized to atreatment sequence according to the random allocation schedule (RAS) asdescribed for Example 26. The treatment sequences for this study arepresented in Table 30.1.

TABLE 30.1 Period 1 Period 2 Sequence Treatment 1 1× OxyContin ® 40 mg1× Example 14.5 2 1× Example 14.5 1× OxyContin ® 40 mg

Study Procedures

The study included two study periods, each with a single doseadministration. There was a washout period of at least six days betweendose administrations in each study period. During each period, subjectswere confined to the study site from the day prior to administration ofthe study drugs through 48 hours following administration of the studydrugs, and subjects returned to the study site for 72-hour procedures.

At each study period, following a 10 hour overnight fast, the subjectswere fed a standard meal (FDA high-fat breakfast) 30 minutes prior toadministration of either Example 14.5 formulation or OxyContin®40 mgtablets with 240 mL of water. No food was allowed for at least 4 hourspost-dose.

Subjects received naltrexone HCl 50 mg tablets at −12, 0, 12, 24, and 36hours relative to Example 14.5 formulation or OxyContin® dosing.

Subjects were standing or in an upright sitting position while receivingtheir dose of Example 14.5 formulation or OxyContin®. Subjects remainedin an upright position for a minimum of 4 hours.

Fasting was not required for non-dosing study days.

During the study, adverse events and concomitant medications wererecorded, and vital signs (including blood pressure, body temperature,pulse rate, and respiration rate) and SPO₂ were monitored.

Blood samples for determining oxycodone plasma concentrations wereobtained for each subject at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5,4, 4.5, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours postdosefor each period.

For each sample, 6 mL of venous blood were drawn via an indwellingcatheter and/or direct venipuncture into tubes containing K₂EDTAanticoagulant. Plasma concentrations of oxycodone were quantified by avalidated liquid chromatography tandem mass spectrometric method.

The study completion procedures were performed as described for Example26.

The results of this study are shown in Table 30.2.

TABLE 30.2 Statistical Results of Oxycodone Pharmacokinetic Metrics:Bioavailability Example 14.5 Formulation Relative to OxyContin ® 40 mgin the Fed State (Population: Full Analysis) 90% LS Mean^(a) Test/Confidence Metric N (Test)^(b) N (Reference)^(b) Reference^(c)Interval^(d) C_(max) 76 59.8 80 59.9 99.9 (95.40, 104.52) (ng/mL)AUC_(t) 76 514 80 556 92.5 (90.01, 94.99)  (ng * hr/ mL) AUC_(inf) 76516 80 558 92.4 (90.00, 94.96)  (ng * hr/ mL) ^(a)Least squares meanfrom ANOVA. Natural log (ln) metric means calculated by transforming theln means back to the linear scale, i.e., geometric means. ^(b)Test =Example 14.5 tablet; Reference = OxyContin ® 40 mg tablet. ^(c)Ratio ofmetric means for ln-transformed metric (expressed as a percent).Ln-transformed ratio transformed back to linear scale. ^(d)90%confidence interval for ratio of metric means (expressed as a percent).Ln-transformed confidence limits transformed back to linear scale.

The results show that Example 14.5 tablets are bioequivalent toOxyContin® 40 mg tablets in the fed state.

Example 31

In Example 31, a randomized, open-label, single-center, single-dose,two-treatment, two-period, two-way crossover study in healthy humansubjects was conducted to assess the bioequivalence of Example 14.5oxycodone IITC1 (40 mg) formulation relative to the commercialOxyContin® formulation (40 mg) in the fasted state.

The study treatments were as follows:

Test treatment: 1× Example 14.5 tablet (40 mg oxycodone HCl)Reference treatment: 1× OxyContin® 40 mg tablet

The treatments were each administered orally with 8 oz. (240 mL) wateras a single dose in the fasted state.

As this study was conducted in healthy human subjects, the opioidantagonist naltrexone hydrochloride was administered to minimizeopioid-related adverse events.

Subject Selection

Screening procedures were performed as described for Example 26.

Subjects who met the inclusion criteria as described for Example 26 wereincluded in the study. Potential subjects were excluded from the studyaccording to the exclusion criteria as described for Example 26.

Subjects meeting all the inclusion criteria and none of the exclusioncriteria were randomized into the study. It was anticipated thatapproximately 84 subjects would be randomized, with approximately 76subjects targeted to complete the study.

Check-in Procedures

The check-in procedures performed on day −1 of period 1 and at check-infor each period were performed as described in Example 26. Pre-dose (Day−1, Period 1 only) laboratory samples (hematology, biochemistry, andurinalysis) were collected after vital signs and SPO₂ had been measuredfollowing fasting for a minimum of 4 hours.

Prior to the first dose in Period 1, subjects were randomized to atreatment sequence according to the random allocation schedule (RAS) asdescribed for Example 26. The treatment sequences for this study arepresented in Table 31.1.

TABLE 31.1 Period 1 Period 2 Sequence Treatment 1 1× OxyContin ® 40 mg1× Example 14.5 2 1× Example 14.5 1× OxyContin ® 40 mg

Study Procedures

The study included two study periods, each with a single doseadministration. There was a washout period of at least six days betweendose administrations in each study period. During each period, subjectswere confined to the study site from the day prior to administration ofthe study drugs through 48 hours following administration of the studydrugs, and subjects returned to the study site for 72-hour procedures.

At each study period, the subjects were administered the Example 14.5formulation or OxyContin® 40 mg tablets with 240 mL of water, followinga 10 hour overnight fast. Subjects continued fasting from food for atleast 4 hours post-dose.

Subjects received naltrexone HCl 50 mg tablets at −12, 0, 12, 24, and 36hours relative to Example 14.5 formulation or OxyContin® dosing.

Subjects were standing or in an upright sitting position while receivingtheir dose of Example 14.5 formulation or OxyContin®. Subjects remainedin an upright position for a minimum of 4 hours.

Fasting was not required for non-dosing study days.

During the study, adverse events and concomitant medications wererecorded, and vital signs (including blood pressure, body temperature,pulse rate, and respiration rate) and SPO₂ were monitored.

Blood samples for determining oxycodone plasma concentrations wereobtained for each subject at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5,4, 4.5, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours postdosefor each period.

For each sample, 6 mL of venous blood were drawn via an indwellingcatheter and/or direct venipuncture into tubes containing K₂EDTAanticoagulant. Plasma concentrations of oxycodone were quantified by avalidated liquid chromatography tandem mass spectrometric method.

The study completion procedures were performed as described for Example26.

The results of this study are shown in Table 31.2.

TABLE 31.2 Statistical Results of Oxycodone Pharmacokinetic Metrics:Bioavailability Example 14.5 Formulation Relative to OxyContin ® 40 mgin the Fasted State (Population: Full Analysis) 90% LS Mean^(a) Test/Confidence Metric N (Test)^(b) N (Reference)^(b) Reference^(c)Interval^(d) C_(max) 85 46.1 83 47.7 96.6 (92.80, 100.56) (ng/mL)AUC_(t) 85 442 83 463 95.5 (92.93, 98.18)  (ng * hr/ mL) AUC_(inf) 85444 82 468 94.8 (92.42, 97.24)  (ng * hr/ mL) ^(a)Least squares meanfrom ANOVA. Natural log (ln) metric means calculated by transforming theln means back to the linear scale, i.e., geometric means. ^(b)Test =Example 14.5 tablet; Reference = OxyContin ® 40 mg tablet. ^(c)Ratio ofmetric means for ln-transformed metric (expressed as a percent).Ln-transformed ratio transformed back to linear scale. ^(d)90%confidence interval for ratio of metric means (expressed as a percent).Ln-transformed confidence limits transformed back to linear scale.

The results show that Example 14.5 tablets are bioequivalent toOxyContin® 40 mg tablets in the fasted state.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference for all purposes.

1-169. (canceled)
 170. A process of preparing a solid oral extendedrelease pharmaceutical dosage form comprising an extended release matrixcomprising a composition, said process comprising the steps of: (a)combining (1) an opioid or a pharmaceutically acceptable salt thereofwith each of (2) at least one low molecular weight polyethylene oxidehaving, based on rheological measurements, an approximate molecularweight of less than 1,000,000, and (3) at least one high molecularweight polyethylene oxide having, based on rheological measurements, anapproximate molecular weight of 7,000,000 to form at least one blend;(b) applying each said blend to form a shaped tablet; and (c) curingsaid shaped tablet by subjecting the shaped tablet to a temperature fromabout 60 to about 90° C. for a time of from about 15 minutes to about 10hours, wherein said cured shaped tablet comprises at least 72% byweight, based upon the total weight of said composition, of said highand low molecular weight polyethylene oxides.
 171. A process as definedin claim 170, wherein said opioid or pharmaceutically acceptable saltcomprises at least 2.4% by weight, based upon the total weight of saidcomposition.
 172. A process as defined in claim 171, wherein said curingstep comprises one or both of (i) a curing time of 15 minutes to 60minutes and (ii) a curing temperature of 70 to 78° C.
 173. A process asdefined in claim 170, wherein said opioid or pharmaceutically acceptablesalt thereof is combined with said low molecular weight polyethyleneoxide to form a first blend and said opioid or pharmaceuticallyacceptable salt thereof is combined with said high molecular weightpolyethylene oxide to form a second blend, wherein at least one blendfurther comprises at least one additive.
 174. A process as defined inclaim 173, wherein the first blend is applied to form said shaped tabletby compressing the first blend to form a core, and the second blend isapplied to form said shaped tablet by compressing the second blend ontothe core.
 175. A process of preparing a solid oral extended releasepharmaceutical dosage form comprising an extended release matrixcomprising a composition, said process comprising the steps of: (a)combining (1) hydrocodone or a pharmaceutically acceptable salt thereofwith each of (2) at least one low molecular weight polyethylene oxidehaving, based on rheological measurements, an approximate molecularweight of less than 1,000,000 and (3) at least one high molecular weightpolyethylene oxide having, based on rheological measurements, anapproximate molecular weight of 7,000,000 to form at least one blend;(b) applying each said blend to form a shaped tablet; and (c) curingsaid shaped tablet by subjecting the shaped tablet to a temperature fromabout 60 to about 90° C. for a time of from about 15 minutes to about 10hours, wherein said cured shaped tablet comprises at least 72% byweight, based upon the total weight of said composition, of said highand low molecular weight polyethylene oxides, and wherein said lowmolecular weight polyethylene oxide comprises at least 20% by weight,based upon the total weight of said composition.
 176. A process asdefined in claim 175, wherein said curing step comprises one or both of(i) a curing time of 15 minutes to 60 minutes and (ii) a curingtemperature of 70 to 78° C.
 177. A process as defined in claim 175,wherein said at least one blend further comprises at least one additive.178. A process as defined in claim 175, wherein said low molecularweight polyethylene oxide is at least 22% by weight and said highmolecular weight polyethylene oxide is at least 50% by weight, basedupon the total weight of said composition.
 179. A process as defined inclaim 178, wherein said cured shaped tablet comprises at least 79% byweight, based upon the total weight of said composition, of said highand low molecular weight polyethylene oxides.
 180. A process as definedin claim 175, wherein said hydrocodone or pharmaceutically acceptablesalt thereof comprises at least 2.4% by weight, based upon the totalweight of said composition.
 181. A process as defined in claim 175,wherein said hydrocodone or pharmaceutically acceptable salt thereofcomprises at least 5% by weight, based upon the total weight of saidcomposition.
 182. A process as defined in claim 175, wherein saidhydrocodone or pharmaceutically acceptable salt thereof comprises atleast 10% by weight, based upon the total weight of said composition.183. A process as defined in claim 177, wherein said at least oneadditive is selected from microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate, and combinations thereof.
 184. A processas defined in claim 180, wherein said curing step comprises one or bothof (i) a curing time of 15 minutes to 60 minutes and (ii) a curingtemperature of 70 to 78° C.
 185. A process as defined in claim 175,wherein said opioid or pharmaceutically acceptable salt thereof iscombined with said low molecular weight polyethylene oxide to form afirst blend and said opioid or pharmaceutically acceptable salt thereofis combined with said high molecular weight polyethylene oxide to form asecond blend, wherein at least one blend further comprises at least oneadditive.
 186. A process as defined in claim 185, wherein the firstblend is applied to form said shaped tablet by compressing the firstblend to form a core, and the second blend is applied to form saidshaped tablet by compressing the second blend onto the core.
 187. Aprocess as defined in claim 180, wherein said curing step comprises oneor both of (i) a curing time of 15 minutes to 60 minutes and (ii) acuring temperature of 70 to 78° C.
 188. A process as defined in claim186, wherein said curing step comprises one or both of (i) a curing timeof 15 minutes to 60 minutes and (ii) a curing temperature of 70 to 78°C.
 189. A process as defined in claim 180, wherein said cured shapedtablet comprises at least 54% high molecular weight polyethylene oxide.190. A process as defined in claim 175, wherein said cured shaped tabletcomprises at least 80% by weight, based upon the total weight of saidcomposition, of said high and low molecular weight polyethylene oxides.191. A process as defined in claim 175, wherein said cured shaped tabletcomprises at least 90% by weight, based upon the total weight of saidcomposition, of said high and low molecular weight polyethylene oxides.192. A process as defined in claim 180, wherein said cured shaped tabletcomprises at least about 79% by weight, based upon the total weight ofsaid composition, of said high and low molecular weight polyethyleneoxides.
 193. A process as defined in claim 180, wherein said curedshaped tablet comprises at least about 80% by weight, based upon thetotal weight of said composition, of said high and low molecular weightpolyethylene oxides.
 194. A process as defined in claim 180, whereinsaid cured shaped tablet comprises at least about 85% by weight, basedupon the total weight of said composition, of said high and lowmolecular weight polyethylene oxides.
 195. A process as defined in claim180, wherein said cured shaped tablet comprises at least about 90% byweight, based upon the total weight of said composition, of said highand low molecular weight polyethylene oxides.
 196. A process as definedin claim 170, wherein said curing comprises convection curing in aconvection curing device.
 197. A process as defined in claim 186,wherein said at least one additive is selected from microcrystallinecellulose, hydroxypropyl cellulose, magnesium stearate, and combinationsthereof, and said curing comprises convection curing in a convectioncuring device.
 198. A process as defined in claim 187, wherein saidcuring comprises convection curing in a convection curing device.
 199. Aprocess as defined in claim 198, wherein said curing temperaturecorresponds to a mean exhaust temperature of said convection curingdevice during said curing time.